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Sickle Cell Disease—Genetics, Pathophysiology, Clinical Presentation and Treatment

Baba p. d. inusa.

1 Paediatric Haematology, Evelina London Children’s Hospital, Guy’s and St Thomas NHS Trust, London SE1 7EH, UK

Lewis L. Hsu

2 Pediatric Hematology-Oncology, University of Illinois at Chicago, Chicago, IL 60612, USA

Neeraj Kohli

3 Haematology, Guy’s and St Thomas NHS Trust, London SE1 7EH, UK

Anissa Patel

4 Holborn Medical Centre, GP, London WC1N 3NA, UK

Kilali Ominu-Evbota

5 Paediatrics Department, Basildon and Thurrock University Hospitals, NHS Foundation Trust, Basildon SS16 5NL, UK

Kofi A. Anie

6 Haematology and Sickle Cell Centre, London North West University Healthcare NHS Trust, London NW10 7NS, UK

Wale Atoyebi

7 Department of Clinical Haematology, Cancer and Haematology Centre, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital, Oxford OX3 9DU, UK

Sickle cell disease (SCD) is a monogenetic disorder due to a single base-pair point mutation in the β-globin gene resulting in the substitution of the amino acid valine for glutamic acid in the β-globin chain. Phenotypic variation in the clinical presentation and disease outcome is a characteristic feature of the disorder. Understanding the pathogenesis and pathophysiology of the disorder is central to the choice of therapeutic development and intervention. In this special edition for newborn screening for haemoglobin disorders, it is pertinent to describe the genetic, pathologic and clinical presentation of sickle cell disease as a prelude to the justification for screening. Through a systematic review of the literature using search terms relating to SCD up till 2019, we identified relevant descriptive publications for inclusion. The scope of this review is mainly an overview of the clinical features of pain, the cardinal symptom in SCD, which present following the drop in foetal haemoglobin as young as five to six months after birth. The relative impact of haemolysis and small-vessel occlusive pathology remains controversial, a combination of features probably contribute to the different pathologies. We also provide an overview of emerging therapies in SCD.

1. Introduction

Sickle cell disease (SCD) was first reported by Herrick in 1910 even though reports suggest prior description of the disorder [ 1 ]; it is the result of homozygous and compound heterozygote inheritance of a mutation in the β-globin gene. A single base-pair point mutation (GAG to GTG) results in the substitution of the amino acid glutamic acid (hydrophilic) to Valine (hydrophobic) in the 6th position of the β-chain of haemoglobin referred to as haemoglobin S (HbS) [ 2 ]. Phenotypic variation in clinical presentation is a unique feature of SCD despite a well-defined Mendelian inheritance, the first to be molecularly characterised as described by Pauling [ 3 ] and confirmed to be due to a single amino acid substitution by Ingram [ 3 ] almost 70 years ago. SCD is a multi-organ, multi-system disorder with both acute and chronic complications presenting when foetal haemoglobin (HbF) drops towards the adult level by five to six months of age [ 4 ].

2. Classification

The inheritance of homozygous HbS otherwise referred to as sickle cell anaemia (SCA) is the most predominant form of SCD, the proportion varies according the country of origin [ 5 , 6 , 7 ]. The next most common form of SCD is the co-inheritance of HbS and HbC—referred to as HbSC, this is most prevalent in Western Africa, particularly Burkina Fasso and Mali and the coastal countries including Ghana, Benin and Western Nigeria [ 5 , 7 , 8 ]. The co-inheritance with β thalassaemia results in a sickle β thalassaemia genotype ( HbS/βo or HbS/β+ ), depending on the genetic lesion on the thalassaemia component, the clinical presentation may be mild or equally as severe as homozygous SCD (HbS/HbS) [ 9 ]. Those with HbS/βo -thalassaemia have a more severe course of disease similar to homozygous SS patients, while offspring with HbS/β+ -thalassaemia depending on the β-globin mutation is associated with variable phenotype from mild to severe phenotypes SCD [ 3 , 10 ].

3. Epidemiology

SCD is one of the most common inherited life-threatening disorders in human, it predominantly affect people of African, Indiana and Arab ancestry [ 5 , 11 , 12 ]. It is estimated that over 80% of over 300,000 annual births occur in sub-Saharan Africa (SSA), the largest burden from Nigeria and Democratic Republic of Congo [ 13 ]. The gene frequency is highest in West African countries with 1 in 4 to 3 (25–30%) being carriers of HbS compared to 1/400 African Americans and is variable in European populations [ 14 , 15 , 16 ]. The prevalence of SCD in developed countries is increasing partly due to migration from high prevalent countries [ 17 , 18 , 19 , 20 ]. It is estimated that over 14,000 people live with SCD in the UK, similar to France, while countries like Italy, Germany have seen increasing numbers from Africa [ 21 , 22 , 23 , 24 ]. With increasing survival, the age distribution of SCD is changing from a childhood disorder pattern that patients now survive into adulthood and old age. It is now reported that over 94% of those born with SCD now survive into adulthood in the US, France and UK in contrast to the high mortality in SSA where 50–90% may die in the first five years of life [ 12 , 25 , 26 ]. In low resource settings and countries where newborn screening is not yet standard care, patients may die young even before diagnosis is confirmed [ 27 ]. Among the common causes of death in the absence of early diagnosis followed by education and preventive therapies such as penicillin prophylaxis and regular surveillance include infections, severe anaemia (acute splenic sequestration, aplastic anaemia) and multi-organ failure [ 28 ]. It is essential therefore that Newborn and Early Infant diagnosis is given the priority it deserves by those countries where SCD is a public health problem [ 28 , 29 ].The implementation of early infant diagnosis remains out of reach for the majority of countries in SSA despite multiple declarations by international organisations and public statements by politicians to honour such commitments. The benefits for screening can only become meaningful when such practice is embraced by policy-makers across the continent and India where the majority of SCD are born and live. Comprehensive care includes penicillin V prophylaxis, Hydroxycarbamide therapy and preventive therapies such as antimalarials and health promotion where relevant will improve outcomes and health related quality of life [ 30 ].

4. Pathophysiology

The schematic representation in Figure 1 highlights the pathophysiology of SCD [ 31 ]. Red blood cells (RBCs) that contain HbS or HbS in combination with other abnormal β alleles, when exposed to deoxygenated environment undergo polymerisation and become rigid. The rigid RBC’s are liable to haemolysis, and due to increased density may affect blood flow and endothelial vessel wall integrity. The dense rigid RBC’s lead to vaso-occlusion, tissue ischaemia, infarction as well as haemolysis [ 32 ]. The consequence of haemolysis is a complex cascade of events including nitric oxide consumption; haemolysis linked nitric oxide dysregulation and endothelial dysfunction which underlie complications such as leg ulceration, stroke, pulmonary hypertension and priapism [ 33 ]. Unlike normal RBC’s with half-life of approximately 120 days, sickle RBC’s (sRBC) may survive just 10–20 days due to increased haemolysis [ 34 ]. During deoxygenation; healthy haemoglobin rearranges itself into a different conformation, enabling binding with carbon dioxide molecules which reverts to normal when released [ 32 ]. In contrast, HbS tends to polymerise into rigid insoluble strands and tactoids, which are gel-like substances containing Hb crystals. During acute sickling, intravascular haemolysis results in free haemoglobin in the serum, while RBC’s gaining Na + , Ca 2+ with corresponding loss of K + [ 31 ]. The increase in the concentration of Ca 2+ leads to dysfunction in the calcium pump. The calcium depends on ATPase but it is unclear what role calcium plays in membrane rigidity attributed to cytoskeletal membrane interactions. [ 35 ]. Furthermore, hypoxia also inhibits the production of nitric oxide, thereby causing the adhesion of sickle cells to the vascular endothelium [ 33 ]. The lysis of erythrocytes leads to increase in extracellular haemoglobin, thus increasing affinity and binding to available nitric oxide or precursors of nitric oxide; thereby reducing its levels and further contributing to vasoconstriction [ 32 ].

Schematic representation of the pathophysiology (in part) of sickle cell anemia. A single gene mutation (GAG→GTG and CTC→CAC) results in a defective haemoglobin that when exposed to de-oxygenation (depicted in the right half of the diagram) polymerizes (upper right of the diagram), resulting in the formation of sickle cells. Vaso-occlusion can then occur. The disorder is also characterized by abnormal adhesive properties of sickle cells; peripheral blood mononuclear cells (depicted in light blue; shown as the large cells under the sickle cells) and platelets (depicted in dark blue; shown as the dark circular shapes on the mononuclear cells) adhere to the sickled erythrocytes. This aggregate is labelled 1. The mononuclear cells have receptors (e.g., CD44 (labeled 3 and depicted in dark green on the cell surface)) that bind to ligands, such as P-selectin (labeled 2 and shown on the endothelial surface), that are unregulated. The sickle erythrocytes can also adhere directly to the endothelium. Abnormal movement or rolling and slowing of cells in the blood also can occur. These changes result in endothelial damage. The sickled red cells also become dehydrated as a result of abnormalities in the Gardos channel. Hemolysis contributes to oxidative stress and dysregulation of arginine metabolism, both of which lead to a decrease in nitric oxide (NO) that, in turn, contributes to the vasculopathy that characterizes SCD.

5. Disease Modifiers

The sickle β-globin mutation renders the sickle gene pleiotropic in nature, with variable phenotypic expression associated with complex genetic and environmental interactions, as well as disease modifiers that are increasingly being recognised. Sickle RBC (sRBC) polymerisation in deoxygenated environments is influenced by a number of factors including the co-inheritance of alpha thalassaemia, foetal haemoglobin (HbF) level which is determined by a number of genetic factors including genetic variations of BLC11A, HBS1L-MYB and HBB loci and hydroxycarbamide therapy amongst others [ 35 ]. The BCL11A and ZBTB7A genes (LRF protein) are responsible for the suppression of γ chains, and HbF production. HbF reduces sickle cell polymerisation due to reduction in HbS concentration and the fact that it is excluded from the sickle cell polymers. HbF also has high oxygen retention thereby ameliorating both the vaso-occlusive and haemolytic pathology in SCD. Among the four main sickle haplotypes, the level of HbF is highest in the Indian/Arab haplotype [ 8 ] predominantly found in the Arab Peninsula and India followed by the Senegal, and Benin haplotypes most predominant in Sub-Saharan Africa. The Bantu haplotype with the lowest HbF is predominantly found in Central African countries [ 8 , 36 ]. Alpha thalassaemia also modulates the expression of SCD. People with one or two α genes deleted have less haemolysis and fewer vasculopathy complications [ 8 ].

6. Clinical Manifestations

SCD is characterised by protean manifestations ranging from acute generalised pain to early onset stroke, leg ulcers and the risk of premature deaths from multi-organ failure [ 8 ]. As a result of the effect of HbF, clinical features do not begin until the middle to second part of the first year of post-natal life when this has predominantly switched to adult haemoglobin [ 36 , 37 , 38 , 39 , 40 ].

6.1. Vaso-Occlusive Crisis (Pain)

Patients with SCD may experience intense pain early in infancy, childhood and adulthood. Pain usually accounts for the majority of hospitalisations and overall negative impact in patients’ health related quality of life. Pain is the cardinal feature of SCD and it is characteristically unpredictable, episodic in nature, described as one of the most excruciating forms of pain that affects human beings. Pain occurs due to stimulation of nociceptive nerve fibres caused by microvascular occlusion. The microcirculation is obstructed by sRBCs, thereby restricting the flow of blood to the organ and this results in (i) ischaemia, (ii) oedema, (iii) pain, (iv) necrosis, and (v) organ damage [ 10 ]. In the first year of life one of the cardinal features is the ’hand-foot syndrome’ due to vaso-occlusion of post-capillary vasculature resulting in tissue oedema and pain of the extremities [ 41 ]. Infants display their pain nonverbally with irritability and apparent ‘regression’ tendencies such as inability to weight bear, walk or crawl. In older children and adults, vaso-occlusive pain can affect any part of the body. The onset of pain is spontaneous, usually no precipitating factors; well-known triggers include infections, fever, dehydration, acidosis, sudden change in weather including wind speed, cold, rain and air pollution. Resolution of pain is unpredictable. Acute pain might lead to chronic pain [ 42 ].

6.2. Anaemia

Symptomatic anaemia is the commonest symptom in SCD generally more common in SCA (Homozygous S), which usually runs the lowest haemoglobin level common to double heterozygous states. The steady state haemoglobin for asymptomatic patients varies according to the phenotype, ranging from levels as low as 60–80 g/L for homozygous S and / Sβo to 100–110 g/L in double heterozygous SC and Sβ + forms. However, the rate of fall from individual steady state haemoglobin level may trigger symptoms of hypoxia (aplastic crises) or a shock-like state (e.g., acute splenic sequestration) [ 4 , 43 ].

6.3. Acute Aplastic Crisis

The most common cause of acquired bone marrow failure in SCD and other haemolytic disorders is caused by Parvovirus B19 [ 44 ]. This virus causes the fifth disease and normally in healthy children is quite mild, associated with malaise, fever and sometimes a mild rash; the virus affects erythropoiesis by invading progenitors of RBCs in the bone marrow and destroying them, thus preventing new RBCs from being made. There’s a slight drop in haematocrit in children with HbAA who are generally unaffected, however in SCD as the lifespan of RBC’s is reduced to about 10–20 days, there is a significant drop in haemoglobin concentration. Parvovirus B19 infection usually takes about four days to one week to resolve and patients with SCD usually require a blood transfusion [ 39 , 44 ].

6.4. Infection

SCD increases susceptibility to infections, notably bacterial sepsis and malaria in children under five years [ 45 ]. Respiratory infections can trigger the sickle-cell acute chest syndrome, with a high risk of death. Risk factors for infections include: (i) functional asplenia/hyposplenia which present with reduced splenic immune response at a very young age, (ii) impaired fixation of complement, (iii) reduced oxidative burst capacity of chronically activated neutrophils, dysfunctional IgM and IgG antibody responses and defective opsonisation. The main pathogen of concern is Streptococcus pneumoniae, though severe and systemic infections arise with Haemophilus influenzae , Neisseria meningitides , and Salmonellae leads to osteomyelitis especially Salmonella due to bowel ischaemia and gut flora dissemination [ 46 , 47 ].

6.5. Splenic Sequestration Crisis

The main function of the spleen is the removal of defective red blood cells including sickled RBCs (sRBC) resulting in further haemolysis [ 48 ]. Blood flow through the spleen is slow reducing oxygen tension and increased polymerisation in HbS. As a result of the narrow capillaries in the splenic vascular bed, further hypoxia occurs with RBC polymerisation and entrapment of affected blood cells. This leads to a cycle of hypoxia, RBC polymerisation, and reduced blood flow causing the spleen to enlarge, for unexplained reasons, this may occur suddenly with pooling of blood within the vascular bed resulting in shock and circulatory failure. The rapidly increasing spleen size may lead to abdominal distension, sudden weakness, increased thirst, tachycardia and tachypnoea. Splenic sequestration crisis is an emergency because if left untreated, it can lead to death in 1–2 h due to circulatory failure [ 49 ].

6.6. Other Complications

The complications listed above are highlighted as those affecting babies and young children, because these are immediately relevant after newborn screening. Older children, adolescents, and young adults develop many chronic complications: stroke, cognitive dysfunction, priapism, leg ulcers, avascular necrosis (of the femoral head or humeral head), chronic pain, retinopathy, pulmonary hypertension, acute kidney injury, chronic kidney disease, thromboembolic events, and hepatic sequestration [ 50 , 51 ], cholelithiasis (gallstones) and cholecystitis as a result of excessive production and precipitation of bilirubin due to haemolysis. SCD also increases susceptibility to complications in pregnancy [ 52 ].

6.7. Psychosocial Impact

SCD has a significant psychosocial impact on patients and families [ 53 ]. This mainly results from the effect of pain and symptoms on their daily lives, and society’s attitudes towards them. Cultural factors are particularly important to these problems because of beliefs and practices [ 54 ]. Furthermore, the ability of people with SCD to cope with their condition varies greatly because severity, general health, and quality of life varies greatly among individuals [ 55 , 56 ].

7. Treatment and Management

SCD causes a range of acute and long-term complications, requiring a multi-disciplinary approach, involving various medical specialists. In the United Kingdom, comprehensive SCD care is coordinated by specialist haemoglobinopathy teams [ 57 ]. Such teams play a key role in education about SCD for patients and their families, as well as guiding treatment with disease-modifying therapies, access to psychology, social and welfare support. Additionally, they coordinate screening services such as Transcranial Doppler (TCD) ultrasound monitoring in children, detection of iron overload or allo-antibody formation in individuals on transfusion programmes, and referral to specialists for major organ complications with an interest in SCD.

8. Management of Acute Vaso-Occlusive Crises (Pain)

Pain is the commonest acute complication of SCD, and significantly impact health-related quality of life [ 58 ]. Pain management may vary from patient to patient depending on family dynamics and individual patient thresholds or access to health care, however mild to moderate painful episodes may be treated in the home without the need of attending a health facility. Self-help psychological strategies including distraction techniques such as guided imagery can be a useful evidence-based adjunct to managing pain, and patients who utilise complementary coping strategies tend to require fewer hospitalisations [ 53 , 59 ]. The management strategy for pain includes 4 stages: which are assessment, treatment, reassessment, and adjustment [ 60 ]. It is also important to take into consideration (1) the severity of pain and (2) the patient’s past response to different analgesics and to follow their regular protocols to alleviate the patient’s pain.

Supportive Care

Given the fact that pain is often triggered by infection, exposure to cold or dehydration, supportive care during these episodes involves providing hydration, warmth and treating any treating the underlying infection. Simple devices such as incentive spirometry can be critical in preventing complications such as acute chest syndrome. Longer-term infection prevention varies regionally but can involve vaccination programs and penicillin prophylaxis [ 61 ].

9. Disease Modifying and Curative Treatments

Currently the only available disease-modifying medications for SCD are hydroxycarbamide and l -glutamine. Both are given daily to reduce the rate of acute complications, but results vary from person to person. Another effective disease modifying therapy is blood transfusion to raise the haemoglobin for improved oxygenation in severe anaemia and also to reduce the proportion of sickle haemoglobin (HbS%) may be give as a simple top-up blood transfusion or as exchange transfusion (manual or automated). The main curative therapy is stem cell transplantation while gene therapy is in the horizon in clinical Trials.

9.1. Hydroxycarbamide

Hydroxycarbamide has gained widely accepted use globally [ 62 ]. Although it was originally used as a cytoreductive agent by inhibiting ribonucleotide reductase, the main mechanism through which hydroxycarbamide works in SCD is through increasing total haemoglobin concentration and HbF production [ 63 ]. Hydroxycarbamide also reduces the number of leucocytes in blood, and reduces expression of surface adhesion molecules on neutrophils, red cells and vascular endothelium resulting in improved blood flow and reducing vaso-occlusion [ 62 ]. A number of trials in adults and children have shown beneficial effects of long-term hydroxycarbamide use, including reducing the severity and frequency of crisis in children with SCD [ 64 ]. The Multi-Centre Study of Hydroxycarbamide (MSH) showed that over a two-year follow-up period, adults on hydroxycarbamide had a significantly lower frequency of painful crises compared with placebo (median 2.5 versus 4.5 respectively, p = 0.001), as well as lower incidence of acute chest syndrome (25 versus 51, p = 0.001) and lower need for blood transfusion (48 patients versus 73, p = 0.001). A subsequent observational study following up on participants of the MSH study over a nine-year period showed a 40% reduction in mortality amongst patients on hydroxycarbamide. Patients with SCD who have increased HbF levels suffer less pain and live longer [ 62 ]. A meta-analysis in 2007 looked at effectiveness, efficacy and toxicity of hydroxycarbamide in children with SCD and they found that HbF levels increased by about 10% and also found a significant increase in haemoglobin concentration by approximately 1%; and on average there was a decrease in hospitalisation rates by 71% as well as a decrease in the frequency of pain crisis [ 62 , 65 ]. Indications for Hydroxycarbamide vary according to the phenotype, age and individual practice [ 65 ]. The US National Institute of Health (NIH) evidence-based guidelines and British Society of Haematology recommend offering Hydroxycarbamide to all HbSS and HbS/β0 thalassaemia genotype children from age of 1 year even though actual practice varies widely between continents.

In adults, indications for hydroxycarbamide may include [ 66 , 67 , 68 ]:

• Frequent painful episodes (>3 per annum) or chronic debilitating pain not controlled by usual protocols.
• History of stroke or a high risk for stroke or other severe vaso-occlusive events.
• Severe symptomatic anaemia.
• History of acute chest syndrome.

Patients on hydroxycarbamide undergo regular monitoring for the development of leucopenia and/or thrombocytopenia. Hydroxycarbamide can cause birth defects in animal models, hence the caution about its use during pregnancy, but hydroxycarbamide has not yet been linked to birth defects in humans. Short term research has shown only minor side effects and the benefits of using hydroxycarbamide outweigh any short-term adverse effects [ 62 , 65 ].

9.2. l -Glutamine

Glutamine is a conditionally essential amino acid, meaning that although the body normally makes sufficient amounts, at times of stress the body’s need for glutamine increases, and in such instances, it also relies on dietary glutamine to meet this demand. The U.S. Food and Drug Administration (FDA) approved use of pharmaceutical-grade l -glutamine for sickle patients aged five years or older in July 2017 [ 69 ]. Formal clinical trials showed that this purified version of glutamine significantly reduced the frequency of acute complications of SCD. Side effects appear to be minor and do not require lab monitoring [ 31 , 69 ].

FDA approval was based on the results of two double-blind randomized placebo-controlled trials studying the effect of l -glutamine on clinical end-points in adults and children over five years old with HbSS or HbS/βo thalassaemia. A phase III double-blind placebo-controlled trial randomising two hundred and thirty patients aged 5 to 58 years in a 2:1 ratio to either 0.3 g/kg oral l -glutamine twice daily, rounded to 5 g doses to a maximum of 30 g, or placebo. Concerns around the study results are due to the high dropout rate, with 97 (63.8%) participants in the intervention group and 59 (75.6%) in the placebo group completing the eleven-month study. The researchers showed a 17.9% reduction in the mean frequency of sickle crises in the l -glutamine group (3.2 versus 3.9 in the l -glutamine and placebo groups respectively ( p = 0.0152)) and significantly fewer pain crises in the l -glutamine group (median 3.0 in the l -glutamine group and 4.0 in the placebo group, p = 0.005). There was significantly fewer hospitalisations in the l -glutamine group (median 2.0 in the l -glutamine group and 3.0 in the placebo group, p = 0.005) [ 69 ]. There were also significant reductions in the frequency of acute chest crises (8.6% on the l -glutamine group versus 23.1% in the placebo group, p = 0.003), and duration of hospital admissions (median 6.5 in the l -glutamine group versus 11 in the placebo group, p = 0.02) [ 69 ]. Potential concerns around use include the lack of long-term follow up data, financial cost compared with hydroxycarbamide, and theoretical concern around reducing treatment concordance with hydroxycarbamide therapy amongst patients seeking more naturalistic medication [ 70 ].

9.3. Blood Transfusion

Individuals with SCD have a baseline level of anaemia due to their chronic haemolysis. Blood transfusions are not given to correct this baseline anaemia or for acute pain episodes. Instead, transfusions are given to correct acute severe anaemia where the haemoglobin falls significantly below that individual’s baseline, and the resulting impairment in oxygen delivery to body tissues would otherwise propagate further sickling of deoxygenated Hb. Examples include red cell aplasia caused by Parvovirus B19 infection, acute splenic sequestration or hyperhaemolysis crises [ 71 ]. In an acute setting, transfusion is also used to bridge periods of severe physiologic stress like major surgery or critical illness including acute chest crises. In this setting, blood transfusion with HbS-negative blood reduces the proportion of circulating haemoglobin that is able to sickle, and hence reducing vessel occlusion and haemolysis from abnormal sickle RBCs. Long-term transfusions are instituted as a disease-modifying treatment in specific situations, such as to prevent stroke. The issues that arise as a result of long term transfusion complications include: (i) Allo-immunization, where after receiving a blood transfusion an individual develops antibodies to an antigen on the transfused red cells, which can increase the risk of having haemolytic reactions to blood that they are transfused in future; (ii) Iron overload, although treatment of iron overload is becoming more tolerable with the new oral chelators and, (iii) Risk of transfusion-transmitted infections, especially in countries where only limited screening of donated blood is available [ 39 , 72 ].

9.4. Bone Marrow Transplantation (BMT)

BMT is the only current cure for SCD and is one of the newer methods of treatments available. Results indicate an event-free survival rate of approximately 91% and a mortality rate of less than 5% [ 51 ]. BMT carries significant risks, such as the new bone marrow producing leucocytes attacking hosts tissue cells which is known as Graft-versus-host-disease (GVHD) [ 73 ]. Tissues affected include skin, liver, gastrointestinal tract and eyes, symptoms include nausea, weight loss and jaundice. The risk of developing GVHD is low when the donor and the recipient are related and matched for HLA type. When the donor and recipient aren’t related or there is a mismatch in HLA types, there is greater the likelihood of developing GVHD; strategies for careful immunosuppression after transplant can reduce the risk of GVHD [ 74 ]. Other risks from undergoing BMT include strokes, fatal infection, organ damage, and fits. Thus, BMT requires specialist centres with highly experienced teams and advanced technological resources. Due to the current levels of risk, a bone marrow transplant is only usually recommended if the symptoms and complications of SCD are severe enough to warrant the risks of BMT [ 75 ].

10. New and Emerging Therapies for Sickle Cell Disease

Researchers are studying several novel and existing medicines for SCD, in order to address different pathophysiological mechanisms. Candidates in the “pipeline” of clinical studies include adhesion blockers, HbS polymerization blockers, antioxidants, regulators of inflammation and activation, and promoters for nitric oxide. Developing a range of mechanistic targets may allow combination therapies to be developed, both to prevent and to treat acute sickle cell complications. For this reason, many phase II and III studies have included patients already established on hydroxycarbamide, to see if combination treatments can provide additional benefit. Examples of some of the key agents under investigation are discussed below.

10.1. Treatments that Reduce HbS Polymerisation

GBT440 (Voxelotor) is an oral small molecule designed to increase the oxygen affinity of HbS, shifting the oxygen dissociation curve of oxy-HbS to the left [ 76 ]. It does this by reversibly binding with the N-terminal valine of alpha (α) chain of Haemoglobin, changing its conformational structure and stabilizing the oxygenation form of the molecule. This reduces the concentration of deoxygenated HbS, which is the form of the molecule that polymerises to give the sickle phenotype. An initial phase I/II study showed Voxelotor to be well tolerated, with predictable pharmacodynamics and pharmacokinetics [ 76 ].

10.2. Nutritional Supplements

Omega-3 fatty acids have been purified from fish oil and tested for benefits as antioxidant, antithrombotic, and anti-inflammatory benefit. The clinical trials have used products with different purity, different proportions of types of omega-3 fatty acids, and different dosages. A trial in Georgia showed significantly decreased pain and decreased platelet activation in adults with sickle cell anemia on large daily quantities of fish oil capsules compared to adults on large daily quantities of olive oil capsules as placebo control [ 31 , 77 , 78 ]. A large trial in Sudan showed school absences were significantly decreased in children with sickle cell anemia taking fish oil compared to those taking placebo [ 77 ].

Folic acid is widely prescribed for SCD with the rationale that increased erythropoiesis causes increased risk of folate deficiency. A Cochrane Review evaluated the one double-blinded placebo-controlled clinical trial that was conducted in the 1980’s and concluded that the trial presents mixed evidence of benefit in children and no trials were found in adults [ 79 ]. Although the Cochrane reviewers recommend further investigation, they also state that no further trials of folic acid in SCD are expected [ 79 ].

EvenFlo, an herbal mixture marketed online by Healing Blends, is the only one of several herbal supplements to begin clinical trials. An open-label observational study was published online by the company in 2017 [ 78 ] and https://healingblendsglobal.com/2017/02/clinical-study-evenflo/ . A randomized controlled trial was recently completed and submitted for peer reviewed publication, still pending at the time of this writing.

A traditional herbal product used to treat SCD in Nigeria, Niprisan, showed promising pre-clinical data although it is likely to have drug interactions from its significant inhibition of cytochrome CYP3A4 activity. Niprisan was awarded “Orphan Drug Status” by the FDA [ 32 , 80 ]. However, financial barriers halted production and Niprisan has not progressed to clinical trials [ 81 ].

10.3. Agents that Reduce Cell Adhesion to Activated Microvascular Endothelium: Targeted Selectin Inhibitors (Crizanlizumab, Rivipansel, Heparins and Heparin-Derived Molecules)

Selectins are transmembrane glycoproteins that are important for cell trafficking for the innate immune system, lymphocytes and platelets. Different families of selectins are expressed on endothelial cells, leucocytes and platelets. Leucocyte rolling and tethering by P and E-selectin, expressed on the surface of activated microvascular endothelium may contribute to reduced blood flow velocity and increased sickling and vaso-occlusion. Therefore, targeted P-selectin inhibitors (Crizanlizumab (SEG101, previously SELG1)), pan-selectin inhibitors (Rivipansel/GMI-1070) have undergone phase II trials. Crizanlizumab was evaluated in a double-blind, randomized, placebo-controlled phase II trial which assigned participants aged 16 to 65 years to either low-dose intravenous Crizanlizumab (2.5 mg/kg), high-dose intravenous Crizanlizumab (5.0 mg/kg), or placebo, administered over 30 min, 14 times throughout the course of one year. Results showed that a 43 percent relative risk reduction in annual acute pain episodes (1.63 vs. 2.98) occurred when comparing the high-dose Crizanlizumab and placebo treatment groups ( p = 0.01). Not only did the therapy decrease the annual acute pain episode rate, but the high dose of Crizanlizumab also delayed the first and second acute pain episodes when compared with placebo (first episode, 4.07 months vs. 1.38 months, p = 0.001; second episode, 10.32 months vs. 5.09 months, p = 0.02; respectively [ 31 , 82 ].

Heparins are able to bind selectins and it has been posited that this allows heparins to reduce sickle cell adhesion to activated endothelium. A double-blind placebo-controlled randomised trial reported a statistically significant reduction in duration of painful crisis and duration of hospital admission with use of tinzaparin, a low molecular weight heparin, compared with supportive care only, amongst 253 patients with SCD admitted with acute painful crisis. Sevuparin is a novel heparin-derived compound in which the anticoagulant effect has been removed, but which retains the selectin-binding effect of heparins [ 83 , 84 ].

10.4. Agents that Improve Blood Flow through Anticoagulant Effect: Antiplatelet and Anticoagulant Agents

10.4.1. prasugrel.

Prasugrel inhibits ADP-mediated platelet aggregation. Previous research suggested that activated platelets adhere to endothelium during vaso-occlusive episodes and recruit leucocytes. A phase III study of 341 children with SCD did not show a significant reduction in vaso-occlusive events per person-year in children taking Prasugrel compared with those taking placebo. It also did not show a significant reduction in diary-reported pain events [ 85 , 86 ].

10.4.2. Apixaban

Apixaban is an oral direct Factor Xa inhibitor, which therefore prevents the activation of prothrombin to thrombin. A phase III randomised placebo-controlled trial is underway investigating the effectiveness of prophylactic dose Apixaban at reducing mean daily pain scores in adults with SCD [ 87 ].

10.5. Agents that Restore Depleted Nitric Oxide within the Microvasculature: Statins, l -Arginine, PDE9

Nitric oxide released from endothelium promotes vessel smooth muscle relaxation, resulting in vasodilatation and improved blood flow. It also suppresses platelet aggregation, as well as reducing expression of cell adhesion molecules on endothelium and reducing release of procoagulant factors. Intravascular haemolysis results in release of free haemoglobin into the patient’s plasma [ 63 ]. This acts as a nitric oxide scavenger. In addition, arginase released from lysed red cells breaks down arginine, which is a substrate used to make endogenous nitric oxide. Both these events result in depletion of nitric oxide levels. Two drug groups that have been investigated for their effect on improving nitric oxide reserves in SCD are statins and l -arginine. Statins inhibit Rho kinase resulting in endothelial nitric oxide synthase activation [ 35 , 88 ].

10.6. Gene Therapy

Gene therapy is in early studies as a possible cure for sickle cell anaemia. The approach is based on stem cells and gene therapy; instead of using embryonic stem cells, host stem cells are derived by manipulating and reprogramming cells from patient’s own blood cells with genetic engineering used to correct the inborn genetic error. Because the cells are provided by the patient, there is no need to find another person to serve as a donor of stem cells and there should be no risk of GVHD. The aim is to transform a patient’s blood cells into pluripotent stem cells and replace the defective portion of the gene. These cells will then be coaxed into becoming hematopoietic cells which can specifically regenerate the entire range of red blood cells. At the time of this writing, a handful of people have apparently been cured of SCD in three gene therapy clinical studies with different lentiviral vectors [ 89 ].

A number of new sickle cell therapeutic options are on the horizon; the promise of combination therapy is no longer a far-fetched aspiration. This calls for an urgent debate with regards to the correct combinations, the right patient phenotype and access for the majority of patients. It is therefore timely to commission such a review on newborn sickle cell screening not just for European countries which of course face the migration challenge, but also Africa and India [ 90 ].

Acknowledgments

Temiladeoluwa Bademosi who wrote an essay on a related topic in sickle cell disease as a medical student.

Author Contributions

B.P.D.I. designed the manuscript which was reviewed by L.L.H., W.A., N.K., K.A.A. offering substantial modification and further development of sections. A.P. had written an essay of the role of thrombosis in SCD, some of the concepts were included. K.O.-E. reviewed the manuscript. All authors approved the manuscript.

This research received no external funding.

Conflicts of Interest

B.P.D.I. receives educational grant from Global Therapeutics, Pfizer, Novartis plc Cyclerion and honorarium from Novartis plc. L.L.H. is a consultant for Hilton Publishing, Pfizer, AstraZeneca, Emmaus, Emmi Solutions, and University of Cincinnati.

Sickle Cell Disease

Mar 23, 2019

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Sickle Cell Disease. Hemoglobin. Protein made of many amino acids The sequence of amino acids is genetic coded by DNA Function to carry oxygen and other compounds. Genetic Process. DNA contains compounds called bases– adenine, thymine, guanine and cytosine– in a genetic coded sequence

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Hemoglobin • Protein made of many amino acids • The sequence of amino acids is genetic coded by DNA • Function to carry oxygen and other compounds

Genetic Process • DNA contains compounds called bases– adenine, thymine, guanine and cytosine– in a genetic coded sequence • mRNA– matches up to those bases and reads the message– where an adenine/thymine, guanine/uracil etc • Moves to cytoplasm of cell and waits for t-RNA carrying the amino acid to find the right sequence and drop off its amino acid

www.vcbio.science.ru.nl/ images/cellcycle/mcel...

http://fig.cox.miami.edu/~cmallery/150/chemistry/hemoglobin.jpg http://fig.cox.miami.edu/~cmallery/150/chemistry/hemoglobin.jpg

Normal Pathology • Inherit 2 copies of the gene called Alleles • When born have Hemoglobin F • By 3 months replaced by Hemoglobin A

Sickle Cell • Caused by a SNP– single nucleotide polymorphism • DNA has Adenine (A base) replaced by Thymine (T base) • So Code is GTG instead of GAG • Valine get put in place of Glutamic acid in 6th amino acid of both beta chains

Sickle Cell continued • Under certain conditions such as low O2 , the hemoglobin molecules stick together or polymerize • Stretches the Red Blood Cells to look like a “sickle” • Affects about 8-11% of African Americans

http://www.healthsystem.virginia.edu/internet/hematology/HessImages/Sickle-Cell-Disease-40x-website.jpg http://www.healthsystem.virginia.edu/internet/hematology/HessImages/Sickle-Cell-Disease-40x-website.jpg

Problems • Cells can’t move thru microvessels • Blood get thick or viscous • Spleen removes the defective cells • Stroke • Infections • Difficulty breathing • Pain • Organ failure or damage

Treatment • Antibiotics started very early in children • Transfusions • Drugs to Aid in production of Hemoglobin F • Hydroxyurea • Butyrate • IV dose and oral 30-40 tablets per day • Pulse therapy • Bone Marrow Transplantation

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What is Sickle Cell Disease?

Sickle cell disease (SCD) is a group of inherited red blood cell disorders. Red blood cells contain hemoglobin, a protein that carries oxygen. Healthy red blood cells are round, and they move through small blood vessels to carry oxygen to all parts of the body. In someone who has SCD, the hemoglobin is abnormal, which causes the red blood cells to become hard and sticky and look like a C-shaped farm tool called a “sickle.” The sickle cells die early, which causes a constant shortage of red blood cells. Also, when they travel through small blood vessels, they get stuck and clog the blood flow. This can cause pain and other serious complications (health problems) such as infection, acute chest syndrome and stroke.

Types of SCD

There are several types of SCD. The specific type of SCD a person has depends on the genes they inherited from their parents. People with SCD inherit genes that contain instructions, or code, for abnormal hemoglobin.

Below are the most common types of SCD:

People who have this form of SCD inherit two genes, one from each parent, that code for hemoglobin “S.” Hemoglobin S is an abnormal form of hemoglobin that causes the red cells to become rigid, and sickle shaped. This is commonly called sickle cell anemia  and is usually the most severe form of the disease.

People who have this form of SCD inherit a hemoglobin “S” gene from one parent and a gene for a different type of abnormal hemoglobin called “C” from the other parent. This is usually a milder form of SCD.

Did you know SCD affects people from many parts of the world?

HbS beta thalassemia

People who have this form of SCD inherit a hemoglobin “S” gene from one parent and a gene for beta thalassemia, another type of hemoglobin abnormality, from the other parent. There are two types of beta thalassemia: “zero” (HbS beta 0 ) and “plus” (HbS beta + ). Those with HbS beta 0 -thalassemia usually have a severe form of SCD. People with HbS beta + -thalassemia tend to have a milder form of SCD.

There also are a few rare types of SCD, such as the following:

Hbsd, hbse, and hbso.

People who have these forms of SCD inherit one hemoglobin “S” gene and one gene that codes for another abnormal type of hemoglobin (“D”, “E”, or “O”). The severity of these rarer types of SCD varies.

Sickle Cell Trait (SCT)

People who have sickle cell trait (SCT) inherit a hemoglobin “S” gene from one parent and a normal gene (one that codes for hemoglobin “A”) from the other parent. People with SCT usually do not have any of the signs of the disease. However, in rare cases, a person with SCT may develop health problems; this occurs most often when there are other stresses on the body, such as when a person becomes dehydrated or exercises strenuously. Additionally, people who have SCT can pass the abnormal hemoglobin “S” gene on to their children.

Learn more about sickle cell trait »

Cause of SCD

SCD is a genetic condition that is present at birth. It is inherited when a child receives two genes—one from each parent—that code for abnormal hemoglobin.

SCD is diagnosed with a simple blood test. In children born in the United States, it most often is found at birth during routine newborn screening tests at the hospital. In addition, SCD can be diagnosed while the baby is in the womb. Diagnostic tests before the baby is born, such as chorionic villus sampling and amniocentesis , can check for chromosomal or genetic abnormalities in the baby. Chorionic villus sampling tests a tiny piece of the placenta, called chorionic villus. Amniocentesis tests a small sample of amniotic fluid surrounding the baby.

Because children with SCD are at an increased risk of infection and other health problems, early diagnosis and treatment are important.

Talk to your doctor to find out how to get tested and to explain the results after testing .

View and print

Complications

People with SCD may start to have signs of the disease during the first year of life, usually around 5 months of age. Symptoms and complications of SCD are different for each person and can range from mild to severe. Learn about the complications.

Prevention and Treatment of SCD Complications

General Prevention Strategies

Management of SCD is focused on preventing and treating pain episodes and other complications. Prevention strategies include lifestyle behaviors as well as medical screening and interventions to prevent SCD complications.

Lifestyle Behaviors

There are simple steps that people with SCD can take to help prevent and reduce the occurrence of pain crises, including the following:

• Drink plenty of water.
• Try not to get too hot or too cold.
• Try to avoid places or situations that cause exposure to high altitudes (for example, flying, mountain climbing, or cities with a high altitude).
• Try to avoid places or situations with exposure to low oxygen levels (for example, mountain climbing or exercising extremely hard, such as in military boot camp or when training for an athletic competition).

Simple steps to prevent harmful infections include the following:

• Wash your hands often . Washing hands with soap and clean water many times each day is one of the best ways people with SCD, their family members, and other caregivers can help prevent an infection.
• Prepare food safely . Bacteria can be especially harmful to children with SCD.

Medical Screenings & Interventions to Prevent SCD Complications

Prevention of Infections

• Vaccines can protect against harmful infections. It is important that children with SCD get all regular childhood vaccines . Similarly, it is important for children and adults to get the flu vaccine every year, as well as the pneumococcal vaccine and any others recommended by a doctor.
• Penicillin greatly reduces the risk of infections in people with HbSS and has been shown to be even more effective when it is started earlier. To decrease the risk of infection, it’s important that young children with HbSS take penicillin (or other antibiotic prescribed by a doctor) every day until at least 5 years of age. Penicillin on a daily basis is usually not prescribed for children with other types of SCD unless the severity of the disease is similar to that of HbSS, such as HbS beta 0 -thalassemia.

Prevention of Vision Loss

• Yearly visits to an eye doctor to look for damage to the retina (the part of your eye that senses light and sends images to your brain) are important for people with SCD to avoid vision loss. If possible, it’s best to see an eye doctor who specializes in diseases of the retina.
• If the retina is damaged by excessive blood vessel growth, laser treatment often can prevent further vision loss.

Prevention of Stroke

• Children who are at risk for stroke can be identified using a special type of exam called transcranial Doppler ultrasound (TCD). If the child is found to have an abnormal TCD, a doctor might recommend frequent blood transfusions (a procedure in which new blood is put into a person’s body through a small plastic tube inserted into a person’s blood vessels) to help prevent a stroke.
• People who have frequent blood transfusions are usually watched closely because there can be serious side effects. For example, because blood contains iron, transfusions can lead to a condition called iron overload, in which too much iron builds up in the body. Iron overload can cause life-threatening damage to the liver, heart, and other organs. Therefore, it is important for people with SCD receiving regular blood transfusions to also receive treatment to reduce excess iron in the body. This type of treatment is known as iron chelation therapy.

Prevention of Severe Anemia

• Blood transfusions may be used to treat severe anemia. A sudden worsening of anemia resulting from infection or enlargement of the spleen (an organ in the upper left side of the abdomen) is a common reason for a transfusion.
• As with preventing stroke, frequent blood transfusions can cause iron overload, and iron chelation therapy may be needed to reduce excess iron in the body.

Management of Pain Crises

When pain crises do occur, clinical management may include the following:

• Intravenous fluids (giving fluids directly into a person’s vein)
• Pain-reducing medicine
• Hospitalization for severe pain crises

Specific Treatments to Prevent SCD Complications

SCD is a disease that worsens over time. Treatments are available that can prevent complications and lengthen the lives of those who have this condition. These treatment options and their effects can be different for each person, depending on the symptoms and severity of their disease. It is important to understand the benefits and risks of each treatment option. Currently, the FDA has approved four treatments for SCD [1] .

• Hydroxyurea (pronounced “hi-DROK-see-yoo-REE-uh”) may help people with SCD ages 2 years and older. More information about hydroxyurea can be found here .
• L-glutamine (pronounced “L-gloo-ta-meen,”), or ENDARI® may help people with SCD ages 5 years and older. More information about L-glutamine can be found on page 2 here .
• Voxelotor (pronounced “vox-EL-o-tor”), or OXBRYTA® may help people with SCD ages 4 years and older. More information about Voxelotor can be found on the FDA website here .
• Crizanlizumab (pronounced “criz-an-liz-u-mab”), or ADAKVEO® may help people with SCD ages 16 years and older. More information about Crizanlizumab can be found on page 1 here .

Several other treatments and therapies for SCD have recently been developed that are still undergoing clinical trials and thus have not yet been approved by the FDA.

The only therapy approved by the FDA that may be able to cure SCD is a bone marrow or stem cell transplant.

Bone marrow is a soft, fatty tissue inside the center of the bones, where blood cells are made. A bone marrow or stem cell transplant is a procedure that takes healthy cells that form blood from one person—the donor—and puts them into someone whose bone marrow is not working properly.

Bone marrow or stem cell transplants are very risky and can have serious side effects, including death. For the transplant to work, the bone marrow must be a close match. Usually, the best donor is a brother or sister. Bone marrow or stem cell transplants are most common in cases of severe SCD for children who have minimal organ damage from the disease.

Find clinical treatment guidelines for providers as well as patient and family resources derived from clinical treatment guidelines:

For healthcare providers.

• Evidence-Based Management of Sickle Cell Disease: Expert Panel Report, 2014, National Heart, Lung, and Blood Institute
• Clinical Practice Guidelines on Sickle Cell Disease, American Society of Hematology

For People with SCD and their Families

• Steps to Better Health for People with Sickle Cell Disease Toolkit

[1] CDC will periodically review and update this treatment list when new treatments are approved by the FDA.

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Sickle Cell Disease: Pathophysiology and Presentation

Neil B. Minkoff, MD: What’s the underlying pathology or pathophysiology that’s leading to all of this cost?

Ahmar U. Zaidi, MD: Our understanding of what exactly is happening in sickle cell disease has taken off in the past 2 decades. We’ve always known that the polymerization of sickle hemoglobin is the mainstay of what’s causing red blood cells to change their shape. But over the past 20 years we’ve learned that the pathophysiology of sickle cell disease is particularly complicated and involves more than just the erythrocytes, and probably involves the endothelium, white blood cells, platelets, overall inflammation, and thrombophilia. The basic issue with sickle cell disease is what we refer to as vaso-occlusion, and that’s driven by a multitude of factors.

Neil B. Minkoff, MD: What is the hemolysis effect?

Ahmar U. Zaidi, MD: Sickle hemoglobin causes, as we discussed, the formation of a long strand polymer that makes sickle cells rigid. And by default, the erythrocytes are required to be able to change shape as they traverse through the various sized vasculature in our body, and they should be able to make it through different types of environments.

What happens is as sickle cells continue to form these polymers, they become unable to get through, they lose their competency to get through the vasculature. Along with that, from the vaso-occlusion we have this effect of ischemia and reperfusion that causes an environment that’s unfavorable for the red blood cell. The result of this is that as sickle cells age, they don’t make it to the expected red blood cell lifespan that we know of, their lifespan is probably reduced by about 75%.

The red blood cells eventually break open and release the content. And the content inside the red blood cells can be quite toxic to the body. They release a variety of molecules that signal to the body that something bad is happening, and the body reacts to that signaling.

Neil B. Minkoff, MD: How does the body react?

Ahmar U. Zaidi, MD: The way the body reacts to that is by identifying that something has gone wrong in the process of the erythrocyte making it through the body. So what we see is an amped-up immune system, and we start seeing consumption of some of the factors that are good for the vasculature in general. So we see the consumption of things like nitric oxide, which is responsible for causing vasodilation, and we end up getting a vasculature that’s inflamed and constricted that makes it even more difficult for erythrocytes make it through.

Neil B. Minkoff, MD: Which sounds like quite the setting for some pretty dramatic complications.

Ahmar U. Zaidi, MD: Absolutely.

Neil B. Minkoff, MD: What are those sort of comorbidities that are caused by this?

Ahmar U. Zaidi, MD: The top flagship comorbidity that’s associated with sickle cell disease is pain. We see tremendous amounts of unpredictable, complex pain that is treated with large doses of opioids, mostly because we don’t have anything better at this point to treat pain with. We also see a top comorbidity of stroke in these patients. The comorbidities you see are obviously based on where the vasculature is being occluded. It’s distributed by anatomic sites. We see a tremendous amount of lung injury in the form of what we call acute chest syndrome. We see things like leg ulcers, and eventually as patients age, we start seeing multi-organ dysfunction.

Neil B. Minkoff, MD: Is that the usual clinical presentation?

Ahmar U. Zaidi, MD: Even though sickle cell disease is a monogenic disorder, every patient has a very unique phenotype, and we see that there are quite a few modifiers in phenotype. Different patients have different journeys. We see patients who are particularly severe who start presenting early in life, under the age of 1, with tremendous amounts of complications. And then we see patients who may have a beneficial modifier in their pathophysiology that stops the polymerization of sickle hemoglobin, for example. Something like an elevated amount of fetal hemoglobin, and those patients tend to have a milder course. So the patient journey is very individualized based on the environment that their erythrocytes are going through.

John C. Stancil, RPh: I would add that presentation at the hospital or the emergency department with pain crisis is the number 1 reason driver for our medical cost for sickle cell patients. And then that creates that stigma that they’re frequent flyers, they’re drug seeking, which creates a whole other stigma around that population.

Ahmar U. Zaidi, MD: Absolutely. There’s a very interesting study called the PiSCES study by Dr Wally Smith, MD, where he gave pain diaries to his sickle cell patients, and he showed that what we’re seeing as providers is the tip of the iceberg. And really the burden of pain in sickle cell disease is what’s submerged under the water. From the patient perspective, it appears that when you follow the pain diaries, about two-thirds of their pain is actually happening at home. So we’re not even seeing the daily burden that this disease is causing on these patients.

John C. Stancil, RPh: Absolutely.

Ahmar U. Zaidi, MD: We’re only seeing a third of it.

Maria Lopes, MD, MS: This may bring up the opportunity perhaps for Telehealth or diaries that help clarify what is beneath that surface. It may actually lead to the emergency department visit, we can actually do something about that.

Ahmar U. Zaidi, MD: Right.

Maria Lopes, MD, MS: What I was going to comment on was also the chest syndrome, because as you get admitted these patients can also be so labile, and survival and mortality is so high, right? This disease is robbing patients of having a normal life expectancy.

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Researchers identify safety of a potential new treatment to manage complications from sickle cell disease

by University of Maryland School of Medicine

A drug approved to treat pulmonary arterial hypertension may be effective at managing hypertension and end-organ damage in patients with sickle cell disease, according to a new study published in Lancet Haematology .

An early-phase randomized clinical trial involving 130 patients with sickle cell disease found that the drug, called riociguat, was found to be safe to use and well tolerated in these patients and significantly improved their blood pressure. Preliminary efficacy data suggested the medication might improve heart function.

An estimated 100,000 Americans have sickle cell disease, and the disease occurs in about 1 out of every 365 Black or African-American births, according to the Centers for Disease Control and Prevention.

People with sickle cell disease are at high risk for vascular complications that can lead to pulmonary hypertension, stroke, and kidney failure , as well as severe pain when red blood cells block blood flow through tiny blood vessels in the chest, abdomen, and joints. These complications can be worsened by hypertension.

Unfortunately, previous research found that sildenafil, an effective treatment for pulmonary hypertension, caused unacceptable side effects in patients with sickle cell disease. It found that those who took this drug experienced high levels of pain that caused increased admissions to the hospital compared to those who took a placebo treatment .

This new study was designed to test the safety of riociguat and how well it works in preventing or reducing clinical complications for patients with sickle cell disease.

In the study, patients with sickle cell disease and mild hypertension or protein in their urine (an early sign of kidney disease) were randomly assigned to receive either riociguat or a placebo in a double-blind clinical trial.

Both groups received the study drug at a starting dose of 1 milligram, which was gradually increased up to 2.5 milligrams and taken three times a day for 12 weeks. The researchers found that among the participants who took riociguat, 22.7 percent experienced at least one serious adverse event related to the treatment. In comparison, in the group that received the placebo, 31.3 percent of participants had at least one serious adverse event during the study.

The differences were not statistically significant. There were no differences between the two groups in the rates of pain severity, pain interference in their daily lives, and vascular events related to their sickle cell disease. When it comes to the effectiveness of the drug treatment, participants who took riociguat had their blood pressure drop by 8.20 mmHg, while those who took a placebo only saw a decrease of about 1.24 mmHg.

The result was highly statistically significant, meaning riociguat was much more effective at lowering blood pressure compared to the placebo, with a difference of approximately 6.96 mmHg. In summary, riociguat was found to be safe and led to a significant improvement in blood pressure over the duration of the study.

"Our results are encouraging and open the door to larger clinical trials involving this class of drugs in patients with sickle cell disease who have pulmonary hypertension or kidney disease."

"Having a drug that's easy to tolerate can help them better manage their blood pressure and help prevent serious complications down the road," said study leader Mark T. Gladwin, MD, who is the John Z. and Akiko K. Bowers Distinguished Professor and Dean of UMSOM, and Vice President for Medical Affairs at University of Maryland, Baltimore.

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• Maternal and infant outcomes in women with sickle cell disease: a matched cohort study
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• Oishi Sikdar 1 ,
• Hemant Ambulkar 2 ,
• http://orcid.org/0000-0003-2667-2190 Allan Jenkinson 1 ,
• Catherine Hedley 3 ,
• Jemma Johns 3 ,
• Ravindra Bhat 2 ,
• http://orcid.org/0000-0001-5258-5301 Theodore Dassios 1 , 2 ,
• Christopher Harris 1 , 2 ,
• http://orcid.org/0000-0002-8672-5349 Anne Greenough 1
• 1 Department of Women and Children’s Health , King's College London , London , UK
• 2 Neonatal Intensive Care Unit , King's College Hospital NHS Foundation Trust , London , UK
• 3 Department of Obstetrics and Gynaecology , King's College Hospital NHS Foundation Trust , London , UK
• Correspondence to Professor Anne Greenough, Department of Women and Children’s Health, King's College London, London SE5 9RS, UK; anne.greenough{at}kcl.ac.uk

Objective Women with sickle cell disease (SCD) have adverse maternal and infant outcomes. Our aim was to determine whether the outcomes of SCD mothers and their infants differed from African or Caribbean women not affected by SCD and whether there were differences between SCD individuals with the haemoglobin SS (HbSS) or haemoglobin SC (HbSC) genotypes. Furthermore, we wished to determine if any differences related to deprivation.

Design A matched cohort study.

Setting Tertiary perinatal centre in London

Patients 4964 African or Caribbean women without SCD and 148 with SCD.

Main outcome measures Mode of delivery, maternal exchange transfusion, birthweight, neonatal unit admission, neonatal death and deprivation indices

Results SCD women were more likely to be delivered by caesarean section (p<0.001) and had babies of lower birthweight (p<0.001). Their infants were no more likely to be admitted to neonatal intensive care unit or suffer a neonatal death. There were no significant differences between the SCD women and those without SCD in their deprivation index or deprivation decile. The women with the HbSS genotype compared to those with the HbSC genotype were more anaemic (p<0.02), required more exchange transfusions (p<0.001) and were more likely to be delivered by caesarean section (p=0.008). The infant outcomes did not differ significantly between the genotypes.

Conclusions Although, the SCD women, particularly those with the HbSS genotype, had greater morbidity, infant morbidity, and mortality was similar in mothers with the HbSS or HbSC genotypes and those without SCD.

• Neonatology

Data availability statement

Data are available upon reasonable request.

https://doi.org/10.1136/archdischild-2024-326848

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WHAT IS ALREADY KNOWN ON THIS TOPIC

Women with sickle cell disease (SCD) have adverse maternal and infant outcomes.

WHAT THIS STUDY ADDS

SCD women, particularly those with the haemoglobin SS (HbSS) genotype, had greater morbidity, but infant morbidity and mortality was similar in mothers with the HbSS or haemoglobin SC (HbSC) genotypes and those without SCD, as were deprivation indices.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

We speculate that our established multidisciplinary team approach may have resulted in the improved outcomes compared with those reported previously.

Introduction

Women with sickle cell disease (SCD) have adverse maternal and infant outcomes. 1 2 In a retrospective comparative cohort study carried out between 2014 and 2018, an increased rate of complications occurred, which included maternal anaemia, intrauterine fetal demise, low birth weight, neonatal asphyxia, neonatal intensive care unit (NICU) admission, early neonatal death and maternal postpartum severe anaemia.

Such adverse outcomes are particularly likely in women with the HbSS genotype. 3 In Jamaica, screening between 1973 and 1981 detected 149 female babies with homozygous sickle cell (HbSS) disease who were matched by age with 129 female controls with an AA haemoglobin genotype. These individuals were followed prospectively and their outcomes were reported in 2021. 4 Mothers with SS disease had more spontaneous miscarriages, fewer live births and their offspring were more likely to be born prematurely and of low birth weight. They were more likely to have urinary tract infection, pre-eclampsia, retained placenta, sepsis and pregnancy-related deaths. Four of the five deaths were attributable to acute chest syndrome (ACS). There was no significant difference in pregnancy-induced hypertension or postpartum haemorrhage. A matched cohort study in London examined the outcomes between 2007 and 2017 of 131 pregnancies to women with SCD and a comparison group of 1310 pregnancies unaffected by SCD. The SCD women were at higher risk of pre-eclampsia/eclampsia and caesarean birth and their infants were more likely to be small for dates and require NICU admission. Stratification by genotype revealed that the risk of adverse outcomes was highest in the HbSS pregnancies, but pre-eclampsia/eclampsia was more frequently observed in HbSC pregnancies. 5

A national inpatient sample in the USA assessed the association of racial disparities with adverse outcomes in 3901 SCD pregnancies and 742 164 pregnancies with black race and no SCD and non-black controls between 2011 and 2022. Compared with the non-black control group, those with black race and SCD or no SCD were younger and more likely to have public insurance. The maternal mortality rate in deliveries among people with SCD was 26 times greater than the control group and 10 times higher than black people without SCD. 6

Our aim was to determine whether the outcomes of SCD mothers and their infants differed from African or Caribbean women not affected by SCD and if there were differences between SCD individuals with the HbSS or HbSC genotypes. Furthermore, we wished to determine if any differences related to deprivation.

The maternal and infant outcomes of African or Caribbean women without SCD who delivered between 2016 and 2022 were compared with those of 148 African or Caribbean women with SCD delivering between 2012 and 2022 ( table 1 ). Data extraction for the non-SCD women was via Badgernet Clevermed UK (Badgernet) and for the SCD women from case notes review and from 2016 onwards crosschecked with Badgernet. Badger Neonatal, a patient management system, forms a single record of care for all babies within neonatal services throughout the UK. Management of pregnant women with SCD was undertaken by a multidisciplinary team, which included a sickle cell expert and an obstetrician experienced with high-risk pregnancies, which has been the same over the study time period. They had an individualised care plan that included management of acute admissions, analgesia and guidelines for transfusion therapy, if required.

• View inline

Maternal and infant outcomes by SCD status

Socioeconomic inequalities were measured by using an area-level measure of deprivation, the United Kingdom multiple deprivation index (MDI) for 2019. 7 The MDI is made up of seven domains which relate to income deprivation, employment deprivation, health deprivation and disability, education, skills and training deprivation, barriers to housing and services and living environment deprivation and crime. 8 The MDI is measured at a super output area level, which is the smallest area for which these deprivation data are available and correspond to approximately 1500 residents. Each super output area in England is ranked by deprivation score and the areas are divided into 10 groups of approximately equal populations of births: decile number 1 is the most deprived and decile number 10 is the least deprived.

The SCD women were more likely to be delivered by caesarean section (p<0.001) and had babies of lower birth weight, on average by 200 g (p<0.001) ( table 1 ). Their infants, however, were no more likely to be admitted to the NICU or suffer a neonatal death. There were no significant differences in the index of deprivation or the deprivation decile between the women with SCD and those without ( table 1 ).

The women with the HbSS genotype compared with those with the HbSC genotype were more anaemic (p<0.02), required more exchange transfusions (p<0.001) and were more likely to be delivered by caesarean section (p=0.008), but not more likely to develop pre-eclampsia or venous thromboembolism (VTE) ( table 2 ). The infant outcomes, including their birth weight, did not differ significantly between the two groups. There was only one neonatal death in each group and similar numbers of babies were admitted to NICU ( table 2 ). One infant only developed neonatal hyperbilirubinaemia necessitating exchange transfusion due to maternal sickle cell crisis in a mother with the HbSS genotype.

Comparison of maternal and infant outcomes by genotype

We have demonstrated that the SCD women were more likely to be delivered by caesarean section and had lighter babies, but their infants did not suffer greater mortality or morbidity. The SCD women compared with African and Caribbean descent women without SCD had similar indices of deprivation and deprivation deciles demonstrating that our results suggest the impact of SCD per se.

The women with the HbSS genotype compared with those with the HbSC genotype were more anaemic (p<0.02), required more exchange transfusions (p<0.001) and were more likely to be delivered by caesarean section (p=0.008), but their infant outcomes were similar. Our findings of lower birth weight of the infants of SCD mothers are similar to those of an earlier study in which women with SCD, either HbSS or HbSC, compared with mothers with the HbAA genotype, had babies of lower birth weight and lower birth weight centiles. 9 Indeed, in that study, the mean difference in weight was 258 g and approximately 200 g in our study. Abnormal placental development in women with SCD results in maternal vascular malperfusion, demonstrable as high resistance uterine artery waveforms on ultrasound. It is strongly associated with small for gestational age infants, preterm birth and stillbirth. 10 In this study, however, there was no significant difference between the proportions of small for gestational age infants in the two groups. Another explanation for the lower birth weight is that the SCD women delivered on average 1 week earlier.

Women with SCD are at risk of pulmonary complications. A systematic review of 22 studies demonstrated an increased risk of pulmonary thromboembolism (relative risk 7.7). The estimated prevalence of ACS and pneumonia was 6.46%, but with no significant difference in prevalence between HbSS and HbSC genotypes. 11

Comparison of two cohorts who delivered between 2005 and 2016 or between 1979 and 2003 demonstrated that in the latter period, pain crises and caesarean section were more common, but there was a reduction in maternal pulmonary complications and no significant difference in other maternal morbidities. Neonatal outcomes were similar in the two time periods, other than birth weight on average was 220 g greater in the latter period. 12 We report the outcomes of women who delivered between 2010 and 2022 and found that throughout that period caesarean sections were more common in the women with SCD, but there were no significant differences in neonatal mortality or morbidity between women of black race with or without SCD. In a retrospective cohort study carried out between 2014 and 2018, NICU admission and neonatal death were more common in infants of mothers with SCD, but this was in a developing country and the outcomes of only 35 women with SCD were reported. 3 Interestingly, the caesarean rate did not differ between women with or without SCD and 43.3% of the infants suffered from neonatal asphyxia, which explained why more infants of SCD mothers were transferred to the NICU.

Only one infant in our series developed hyperbilirubinaemia necessitating exchange transfusion due to maternal sickle cell crisis in a mother with HbSS genotype. 13 Untreated infants could develop kernicterus or in the absence of classical kernicterus they can develop a spectrum of minor neurological manifestations collectively termed as a syndrome of bilirubin-induced neurological dysfunction. 14 Although this then is a rare complication of maternal SCD, it highlights that infants whose mothers have a high unconjugated bilirubin level need careful monitoring.

In a previous study in a similar inner London city area, adverse maternal outcomes were higher in those with the HbSS genotype as we now report. The HbSC mothers, however, had a higher rate of pre-eclampsia, 5 which is in contrast to our findings. The reason for that difference is unclear, not least it has been postulated that SCD may amplify placental disease and with some suggestion that this may be irrespective of SCD genotype and pre-pregnancy health. 10

This study has many strengths and some limitations. We assessed the outcome of women with SCD and compared it to a large number of women of black race living in the same geographical area. As we had a sizeable number of SCD women, we were able to compare outcomes between those with the HbSS and the HbSc genotypes. Although we assessed the SCD women who delivered over a 12-year period, they were all looked by an MDT with the same constituents. A limitation of our study was that Badgernet was only available for the last 6 years of our study, hence for the first 6 years, we relied on reviewing the case notes. In the second 6 years, however, we had Badgernet available and the results recorded were similar to those recorded in the case notes.

We speculate that our established MDT approach may have resulted in improved outcomes compared with those reported previously. Indeed, it has been stated that women with SCD should have individualised care plans and be managed by a multidisciplinary team. 15

In conclusion, the SCD women, particularly those with the HbSS genotype, had greater morbidity than women of black race without SCD, but no higher deprivation indices. Infant morbidity and mortality, however, were similar in mothers with the HbSS or HbSC genotypes and those without SCD.

Ethics statements

Patient consent for publication.

Not applicable.

Acknowledgments

We thank Kate Greenlees for her help in data collection in the control population.

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Presented at The results of this study were presented as an abstract at the Neonatal Society Autumn Meeting 2023.

Contributors AG, JJ and RB conceived the study. OS, HA, AL and CH collected the data. CH, TD and AG analysed the data. OS wrote the first draft. All authors approved the final version of the manuscript.

Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

Competing interests None declared.

Provenance and peer review Not commissioned; externally peer-reviewed.

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Opinion: The revolutionary sickle cell therapies

E ditor’s Note: Elizabeth Yuko, Ph.D., is a bioethicist and writer whose work has appeared in The New York Times, Rolling Stone, The Washington Post, The Atlantic and elsewhere. She is also an adjunct professor at Fordham University. The views expressed here are hers. Read  more opinion  on CNN.

In December, the  US Food and Drug Administration (FDA) approved  the first two cell-based gene therapies for treating sickle cell disease (SCD) in people ages 12 and older:  Casgevy and Lyfgenia . Since then, questions and concerns have abounded about the cost and accessibility of these treatments — including from Health and Human Services Secretary Xavier Becerra, who has consistently  highlighted the financial barriers  standing between people living with SCD and  these new gene therapies .

While both Casgevy and Lyfgenia are breakthroughs, Casgevy is important for one more reason: It’s the first FDA-cleared clinical use of CRISPR-Cas9 (commonly just referred to as CRISPR) gene editing for the treatment of any condition. (Though Lyfgenia also relies on gene modification, it uses different, better-established technology.)

Gene editing refers to various methods that can be used to introduce, replace or remove DNA sequences in the genomes of organisms — including humans. CRISPR acts like genetic scissors to cut and then edit DNA in a particular spot, and has gained favor among researchers for being easier, faster, more accurate and less expensive than earlier techniques.

This first FDA-approved therapeutic application of CRISPR is, without question, a significant step forward in the field of gene therapy and the practice of medicine. And, like any emerging medical technology, the initial use of the innovative gene editing tool has been met with an amalgam of anticipation and anxiety.

To be sure, there are ethical issues at play — most notably, questions of accessibility of the new multimillion-dollar treatments. But as the gene editing tool becomes part of the toolkit for treating an increasing number of conditions, it’s important not to conflate or even associate this application of CRISPR with more problematic uses of the technology.

Casgevy and Lyfgenia are long overdue

The group of inherited red blood cell disorders  collectively known as SCD  is characterized by abnormalities that make a person’s red blood cells sticky and C-shaped instead of round. These sickle cells cause blockages in a patient’s blood vessels, often resulting in pain and other complications.

The US  Centers for Disease Control and Prevention  estimates that it affects approximately 100,000 people in the United States. SCD is most prevalent among those with African ancestry, according to the  National Heart, Lung, and Blood Institute . A study published in May 2023 indicates that of the nearly 75,000 people hospitalized for SCD in the United States between  2016 and 2018 , 93% were Black. In the US, about  20,000 people  are thought to have a form of the disease severe enough to potentially qualify for these gene-based treatments.

About 20% of SCD patients in the United States have a more severe form of the disease, characterized by frequent, painful episodes, estimates Dr.  David A. Williams , the chief of hematology/oncology at Boston Children’s Hospital and a professor of pediatrics at Harvard Medical School. Williams wasn’t involved in the clinical trials for either of the new gene therapies, but consulted on the regulatory approval process for both manufacturers.

“It’s analogous to the pain that you get with a heart attack — which people often express is the most excruciating pain they’ve ever felt,” he tells me. The recurrence and unpredictability of these agonizing episodes impact virtually every aspect of a person’s life, which can make it difficult to go to school consistently or hold down a job.

Yet, despite its debilitating effects — and the fact that in 1949, SCD became  the first disease identified on a molecular level — research into treatments and cures remained underfunded for decades. This was, in large part, the result of what Harriet A. Washington describes in her book Medical Apartheid, as the “erroneous belief” that SCD “was a racial condition that only struck African Americans.”

While there are  four drugs  used to treat aspects of SCD — three of which were approved between 2017 and 2019 — the only potential cure for the condition has been a stem cell transplant.

Transplants from matched sibling donors have the  best chance of success , but, as Williams points out, it’s estimated that  fewer than 20%  of SCD patients have suitable sibling donors. Though it’s also possible to use stem cells from someone who isn’t related to the recipient, Williams says that “the number of available donors that match a person of African American ancestry or Latinx ancestry is low” and doesn’t meet the demand.

Enter the two newly approved treatments. Though they both involve transplants, a patient’s own stem cells are used — eliminating the need for a donor and the accompanying risks.

While Casgevy uses CRISPR to edit DNA in a patient’s blood stem cells so that they start producing healthy hemoglobin, Lyfgenia uses components from a virus to deliver a new gene to a patient’s blood stem cells that produces healthy hemoglobin.

Having two innovative therapies to treat a disease that affects a chronically underserved demographic is major, overwhelmingly positive news.

CRISPR complicates the conversation

The laser focus on CRISPR has, in many ways, overshadowed the introduction of the long-overdue SCD treatments. Though the FDA’s inaugural approval of a treatment that uses the gene editing tool is, of course, noteworthy, the emphasis placed on CRISPR — which many people understand to have at least some ethically problematic applications — could cast an undeserved shadow over the new therapies.

The confusion often stems from the fact that CRISPR can be used to edit two different categories of cells: germ cells (eggs and sperm), and somatic cells, which make up the rest of the body — including the blood cells Casgevy alters. Editing somatic cells only affects the individual; on the contrary, any changes made to the genetic material of embryos or germ cells are passed on to subsequent generations.

Because of the ethical questions raised when genetic modifications impact not only the patient, but their descendants as well, germline modification has, understandably , received the bulk of the public’s attention  where CRISPR is concerned. And to be clear, that use of the “genetic scissors” is unrelated to their use in Casgevy.

“There’s little controversy over somatic cell gene editing: We’ve been doing that now for many years,” says Williams. “That’s very much in contrast to germ cell gene editing, which is banned.”

The high cost of treatment

At this point, it’s unclear how much SCD patients will have to pay for the treatments, and  whether insurance companies  will cover either. What we do know is that the manufacturers will sell Casgevy and Lyfgenia to wholesalers in the US  — which sell products to pharmacies and medical facilities at a markup — for  $2.2 million  and  $3.1 million , respectively.

The US Department of Health and Human Services  recently announced  that it will introduce a new pricing model in 2025 making Casgevy and Lyfgenia more accessible to the estimated 50% to 60% of people living with SCD enrolled in Medicaid. The release — which also notes that “hospitalizations and other health episodes related to SCD cost the health system almost $3 billion per year” — does not mention anything about making the new therapies affordable for SCD patients who aren’t enrolled in Medicaid. ( Recent reporting from KFF  suggests that Blue Cross Blue Shield will cover these therapies, though the out-of-pocket cost for patients could still be high.)

Bluebird bio, the maker of Lyfgenia  has noted  that the price is “in recognition of the value the therapy may deliver through robust and sustained clinical benefits” and the impact that the treatment could have on reducing the healthcare cost of dealing with the disease over the course of a patient’s lifetime.  Both companies have estimated  the cost of managing SCD to be between $4 million and $6 million over the lifetime of a patient with recurrent pain crises.

The excessively high costs of the new treatments would make them inaccessible to many patients in the US, and even further out of reach for people living in low- and middle-income countries where SCD is much more common.

This is unjust not only because people living in one part of the world aren’t more deserving of treatment than others, but also because it would likely exacerbate existing health disparities — essentially limiting SCD to people with lower incomes.

Weighing risks and benefits

Like any newly approved treatment or procedure, the long-term outcomes of Casgevy and Lyfgenia — including whether they’ll be lifetime cures for SCD, as anticipated — aren’t yet known. While Lyfgenia utilizes a gene therapy technique that’s been used in patients with various genetic disorders  since the 2010s , Dr.  Punam Malik, director of the Sickle Cell Center at Cincinnati Children’s ,  says the CRISPR gene editing approach used in Casgevy is limited to two to three years of clinical experience.

At this point, however, only Lyfgenia carries  a black box warning  from the FDA: the result of two participants in an earlier iteration of Lyfgenia’s clinical trial  dying after being diagnosed with leukemia . (The makers of the drug  suggested  these deaths were not likely related to the gene therapy but may have been linked to the chemotherapy participants needed to prepare for it.)

While  no serious adverse events  were reported during the Casgevy clinical trials, Williams says that it’s not yet known whether CRISPR gene editing in general takes place only where directed, or if it occurs elsewhere in the genome as well. If this “off target” editing takes place, it likely doesn’t occur frequently, as the FDA  hasn’t flagged it as a concern.

Opening the door to future CRISPR therapies

The fact that the first FDA-approved application of CRISPR gene editing is a treatment for SCD wasn’t intended to be a gesture attempting to make up for more than a century of ignoring the condition and patient population. Nonetheless, Williams says “it’s great that it’s happened.”

After the first treatment using CRISPR was granted FDA approval, Williams predicted that the gene editing system would be “applied to other diseases fairly quickly.”  And that has indeed been the case; Not long after, the FDA  cleared the use of a CRISPR  treatment for a second disease: beta thalassemia.

What’s more, preliminary research suggests that therapies using CRISPR-based gene editing  may have the potential to treat  other life-altering hereditary diseases, like Alzheimer’s, Parkinson’s, Huntington’s and cystic fibrosis.

In the meantime, the focus should be on making Casgevy and Lyfgenia — as well as the next generation of SCD gene therapies — more affordable to patients worldwide. There are ways this can be done, Malik says, like making stem cell collections more efficient, and reducing the toxicity of pre-transplant conditioning so that it can be administered in an outpatient setting.

After all, as tempting as it may be to view securing FDA approval as a “mission accomplished” moment of sorts, the reality is that outside of clinical trials, groundbreaking treatments like Casgevy and Lyfgenia can only be as effective as they are accessible.

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UMSOM Researchers Identify Safety of a Potential New Treatment to Manage Complications from Sickle Cell Disease

April 10, 2024 | Deborah Kotz

Treatment for lung condition could help patients with sickle cell disease control complications from hypertension and kidney damage

An estimated 100,000 Americans have sickle cell disease, and the disease occurs in about 1 out of every 365 Black or African-American births, according to the Centers for Disease Control and Prevention . People with sickle cell disease are at high risk for vascular complications that can lead to pulmonary hypertension, stroke, and kidney failure as well as severe pain when red blood cells block blood flow through tiny blood vessels in the chest, abdomen, and joints. These complications can be worsened by hypertension.

Unfortunately, previous research found that sildenafil, an effective treatment for pulmonary hypertension, caused unacceptable side effects in patients with sickle cell disease. It found that those who took this drug experienced high levels of pain that caused increased admissions to the hospital compared to those who took a placebo treatment.

This new study was designed to test the safety of riociguat and how well it works in preventing or reducing the clinical complications for patients with sickle cell disease.

The differences were not statistically significant. There were no differences between the two groups in the rates of pain severity, pain interference in their daily lives, and in vascular events related to their sickle cell disease. When it comes to the effectiveness of the drug treatment, participants who took riociguat had their blood pressure drop by 8.20 mmHg, while those who took a placebo only saw a decrease of about 1.24 mmHg. The result was highly statistically significant, meaning riociguat was much more effective at lowering blood pressure compared to the placebo, with a difference of approximately 6.96 mmHg. In summary, riociguat was found to be safe and led to a significant improvement of blood pressure over the duration of the study.

“Our results are encouraging and open the door to larger clinical trials involving this class of drugs in patients with sickle cell disease who have pulmonary hypertension or kidney disease. Having a drug that’s easy to tolerate can help them better manage their blood pressure and help prevent serious complications down the road,” said study leader Mark T. Gladwin, MD ,  who is the John Z. and Akiko K. Bowers Distinguished Professor and Dean of UMSOM, and Vice President for Medical Affairs at University of Maryland, Baltimore.

Bayer Pharmaceuticals, manufacturer of riociguat, provided funding (as well as the drug and placebo) for the study.

The study was led by the clinical and data coordinating centers at the University of Pittsburgh. Study co-authors included faculty from the University of Illinois at Chicago, Albert Einstein College of Medicine, University of Pittsburgh, Emory University, Duke University, Johns Hopkins School of Medicine, and other institutions.

About the University of Maryland School of Medicine

Now in its third century, the University of Maryland School of Medicine was chartered in 1807 as the first public medical school in the United States. It continues today as one of the fastest growing, top-tier biomedical research enterprises in the world -- with 46 academic departments, centers, institutes, and programs, and a faculty of more than 3,000 physicians, scientists, and allied health professionals, including members of the National Academy of Medicine and the National Academy of Sciences, and a distinguished two-time winner of the Albert E. Lasker Award in Medical Research. With an operating budget of more than $1.2 billion, the School of Medicine works closely in partnership with the University of Maryland Medical Center and Medical System to provide research-intensive, academic and clinically based care for nearly 2 million patients each year. The School of Medicine has nearly $600 million in extramural funding, with most of its academic departments highly ranked among all medical schools in the nation in research funding. As one of the seven professional schools that make up the University of Maryland, Baltimore campus, the School of Medicine has a total population of nearly 9,000 faculty and staff, including 2,500 students, trainees, residents, and fellows. The combined School of Medicine and Medical System ("University of Maryland Medicine") has an annual budget of over $6 billion and an economic impact of nearly $20 billion on the state and local community. The School of Medicine, which ranks as the 8th highest among public medical schools in research productivity (according to the Association of American Medical Colleges profile) is an innovator in translational  medicine, with 606 active patents and 52 start-up companies. In the latest U.S. News & World Report ranking of the Best Medical Schools, published in 2021, the UM School of Medicine is ranked #9 among the 92 public medical schools in the U.S., and in the top 15 percent (#27) of all 192 public and private U.S. medical schools. The School of Medicine works locally, nationally, and globally, with research and treatment facilities in 36 countries around the world. Visit medschool.umaryland.edu .

Deborah Kotz Senior Director of Media Relations Office of Public Affairs & Communications University of Maryland School of Medicine [email protected] o: 410-706-4255 c: 617-898-7955 t: @debkotz2

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