Sickle Cell Research Priorities

ASH has developed the following list of sickle cell disease (SCD) research priorities for the next five years. This list includes unaddressed questions and specific research topics that could move the field forward with the hope of curing SCD in the future. The priorities are not listed in rank order.

A. Identify Predictors of Disease Severity

SCD is highly variable clinically, with some patients having a relatively mild course and extended survival and others having frequent and severe complications along with markedly shortened survival. Over the past several decades, researchers have learned about the effects of hemoglobin gene polymorphisms and hemoglobin F levels on the disease course. However, the evidence suggests that information about the hemoglobin genes alone is not sufficient to understand or predict the course of an individual’s disease. Identification of various predictors of disease severity will be vital in the management and treatment of SCD, especially since more recently, several plasma biomarkers and certain genetic polymorphisms have been proposed to influence specific clinical outcomes, including stroke, sickle cell nephropathy, and survival.

Unaddressed Questions:

1. Can specific biomarkers and/or genetic polymorphisms identify patients at high risk for clinical events, such as acute chest syndrome, vaso-occlusive episode, or progression of SCD nephropathy?
2. Can specific biomarkers and/or genetic polymorphisms identify "responders" vs. "nonresponders" in clinical trials of current and new pharmacologic interventions?
3. Can we more precisely define genotype-phenotype relationships?
4. What is the role of environmental factors and comorbidities in disease progression?
5. What do genetic and biological markers tell us about pathophysiologic mechanisms?

Specific Research Priorities:

1. Studies of biomarkers and/or genetic polymorphisms as means of identifying patients at high risk for clinical events, such as acute chest syndrome, stroke, vaso-occlusive episode, or progression of sickle cell nephropathy.
2. Study of biomarkers and genetic polymorphisms and their relationships to pathophysiologic mechanisms, including new animal or in vitro models of disease mechanisms.
3. Studies of biomarkers or genetic markers in the context of clinical drug trials, in order to determine whether response (or lack thereof) may be predictable, allowing for more personalized therapeutic decisions.

B. Optimize the Use of Existing Therapies

Transfusions and hydroxyurea are the only widely available disease-modifying therapies for SCD, but their effectiveness is currently limited by inadequate utilization, a patient subgroup with less than optimal response, and no FDA-approved adjunct therapies. Evidence-based guidelines are now available for the initiation and use of transfusions and hydroxyurea as well as iron chelation therapy to manage transfusion-acquired hemosiderosis. Emphasis should be placed on improving adherence to these evidence-based therapies and on determining whether these therapies can prevent or even reverse organ dysfunction. In addition, research is needed on new adjunct therapies to blood transfusion and hydroxyurea, as well as disease-specific therapies for co-morbidities such as kidney disease, hypertension, obstructive lung disease and pulmonary hypertension. Further therapeutic trials should include SCD genotypes other than HB SS.

Unaddressed Questions:

1. How to improve adherence to prescribed therapeutic interventions with transfusions, hydroxyurea or chelation?
2. How to determine the safety, dosing, and benefits of hydroxyurea for patients with non-HbSS genotypes, especially HbSC?
3. How to optimally manage specific SCD-related co-morbidities that include, but are not limited to, kidney disease, hypertension, obstructive lung disease and pulmonary hypertension?

Specific Research Priorities:

1. Prospective clinical trials to determine the efficacy of hydroxyurea in patients with HbSC.
2. Longitudinal studies to determine the long-term effects of transfusions and hydroxyurea on preservation or restoration of organ function.
3. Clinical trials to modify disease altering co-morbidities, such as kidney disease, hypertension, obstructive lung disease and pulmonary hypertension.

C. Develop Novel Therapies

To date, only one drug has been approved by the FDA to treat SCD, hydroxyurea; moreover, it is only for adults with clinically severe disease. This generally well-tolerated drug has been shown to reduce, but not abolish, the frequent vaso-occlusive episodes and acute chest syndrome characteristic of SCD across a wide age range from infancy to adulthood. In at least some studies, use of hydroxyurea has also been associated with improved survival. While its use was initially promulgated because it increases hemoglobin F levels in many patients, the drug’s mode of action is likely to be much broader, as it also affects leukocyte count, red cell adhesiveness, and other parameters of disease. New therapies addressing diverse pathophysiologic mechanisms of disease are now in various stages of development. However, while many potential therapeutic targets have been identified in animal and in vitro disease models, it is still unknown which targets would be most useful to address in order to reduce the impact of SCD on patients’ lives.

Unaddressed Questions:

1. Which potentially druggable targets are the most critical to address with new pharmacotherapeutic agents?
2. Of the new therapeutic agents in development, which might be more useful in treating vaso-occlusive crisis or other acute sequelae of SCD and which would be more useful in a prophylactic setting?
3. Are there drugs that would be particularly useful in patients at high risk for specific types of organ damage associated with poor survival (e.g., stroke, nephropathy or pulmonary hypertension)?
4. What new agents could be used in combination, including with hydroxyurea?

Specific Research Priorities:

1. Human and animal studies (not limited to murine models) to identify which druggable targets are the most critical to address with new pharmacotherapeutic agents.
2. Phase III and IV studies to develop evidence-based data for efficacy of various treatments (new and old) in acute vaso-occlusion in humans.
3. Phase II and III studies to impede the progression of SCD nephropathy or to prevent recurrent stroke.

D. Strengthen Curative Therapies

Therapies that seek to cure SCD through the sustained production of healthy red blood cells are now feasible and must be pursued. Hematopoietic stem cell transplantation (HSCT) and gene therapy are two of the potentially curative therapies for patients with SCD.

1. Hematopoietic Stem Cell Transplantation
   Hematopoietic stem cells (HSCs) from the bone marrow of a healthy donor can provide a long-term and often permanent treatment for patients with SCD. Over the last 30 years patients with SCD, mostly children, have successfully undergone HSCT, but current regimens still are associated with some risk of morbidity and mortality. In addition, there are barriers to wider use of HSCT, including availability of a suitable sibling donor, transplant-related complications and limited geographic expertise. While modification of HSCT strategies, including alternate sources of HSCs such as umbilical cord stem cells and use of partially-matched or unrelated HSC donors, have yielded promising results, more translational and clinical research is required. Targeted areas needing immediate attention include HSCT in adults with SCD, less toxic reduced-intensity preparative regimens, more effective control of common transplant related complications, and a greater understanding of transplant-related immunology.
   
   Unaddressed Questions:
   
   1. Can HSCT approaches be optimized further for patients with SCD?
   2. How can HSCT for SCD be made more accessible?
   3. Is there a role for early HSCT in SCD patients without severe complications?
2. Gene Therapy
   Gene therapy encompasses new approaches that can correct or ameliorate genetic conditions such as SCD by modifying individual genes within the patient’s own stem cells. Critical advances in the construction of viral vectors used for gene transfer with increasing efficiency and safety have led to the development of early phase clinical trials. Emerging research on targeted gene-editing strategies to repair defective genes also has great potential to correct fundamental genetic and physiologic processes in SCD. Finally, research using reprogrammed cells such as induced pluripotent stem cells (iPSCs) or induced HSCs is rapidly evolving and could be applicable to SCD.
   
   Unaddressed Questions:
   
   1. Can gene therapy safely provide an adequate and permanent source of adult hemoglobin for patients with SCD?
   2. How will the use of gene-editing to alter the expression of non-globin genes impact the processes underlying SCD?
   
   Specific Research Priority:
   
   1. Application of gene correction/repair strategies to SCD

E. Enhance Pain Research

Pain is the most common clinical manifestation of SCD. Patients experience acute, chronic and acute superimposed on chronic pain. The treatment of pain accounts for a large proportion of emergency department visits and hospitalizations of patients with SCD. The prevalence of pain is underestimated by examining healthcare facility utilization, as patients frequently manage painful events at home without seeking medical care. The scope of the problem is far reaching for patients and families, interfering with quality of life, education, and employment.

Unaddressed Questions:

1. What are the mechanisms for pain associated with vaso-occlusion?
2. What are the mechanisms for the evolution of chronic pain syndromes in SCD?
3. What are the genetic and psychosocial correlates of acute and chronic pain syndromes?

Specific Research Priorities:

1. Basic and clinical studies of neurotransmitters and inflammation in acute and chronic SCD pain.
2. Identification of genetic polymorphisms associated with response to pain and opioid medications.
3. Application of quantitative sensory testing, biomarkers, and neuroimaging to understanding the mechanisms of different pain syndromes.
4. Comparative effectiveness studies of opioids, non-opioids and non-pharmacologic interventions in the management of chronic pain and impact on quality of life.

F. Improve Access to Evidence-Based Care Through Innovative Healthcare Delivery Models

Survival of children with SCD has improved substantially, resulting in an increasing adult population. The majority of adults do not receive medical care at a comprehensive SCD center, and there are an inadequate number of physicians in a community setting with SCD expertise. This disparity results in patients not receiving essential outpatient care and overutilization of emergency department and inpatient services. Preventive interventions are underused and overall health maintenance is compromised.

Unaddressed Questions:

1. What patient-centered healthcare delivery models are effective in providing evidence-based SCD-related interventions?
2. What are optimal approaches for providing timely acute and chronic pain management in a community setting?

Specific Research Priorities:

1. Implementation of sustainable patient-centered medical home models to provide comprehensive evidence-based medical care.
2. Development of programs to link primary care and hematology/oncology physicians to physicians with SCD expertise to improve access to community-based quality care.

G. Determine the Effects of Quality of Care on Quality of Life

Major randomized controlled trials and high quality observational studies in SCD have had a significant impact on mortality and morbidity. However, there is evidence of inadequate uptake of efficacious treatment modalities in the usual care setting as exemplified by the under use of hydroxyurea in adults with SCD. Furthermore, there is substantial burden on healthcare systems, patients and families in the delivery and receipt of certain interventions such as chronic red blood cell transfusion. There is a need to optimize the use of proven therapies and to measure the impact on the patient’s quality of life.

Unaddressed Questions:

1. What are appropriate quality indicators for medical care delivered outside of a comprehensive SCD center?
2. Are outcomes from clinical trials achievable in the community setting?

Specific Research Priorities:

1. Determine the impact of effective therapies on health-related quality of life in usual care settings.
2. Define and validate quality of care indicators in children and adults.
3. Test interventions to overcome barriers to receiving recommended SCD-specific treatment in a community setting.

H. Investment in Sickle Cell Trait Research

While SCD is a relatively rare condition in the United States, sickle cell trait is not. Millions of Americans of many ethnicities and even greater number of people globally are carriers for the genetic mutation in SCD and therefore have sickle cell trait. The implications of sickle cell trait alone, in combination with other genetic tendencies or in response to certain environmental factors, have been the subject of limited and often inconclusive studies. More rigorous epidemiologic, genetic and clinical research studies are needed in areas such as cardiovascular disease, chronic kidney disease, and exercise physiology to ascertain the contribution of sickle cell trait to outcomes and to provide sound evidence-based clinical guidance for very broad populations.

Unanswered Questions:

1. Does sickle cell trait increase the risk for sudden death in connection to vigorous exercise?
2. Does sickle cell trait increase the risk of stokes, blood clots, heart or kidney disease?
3. Does the inherited gene mutation causing sickle cell trait interact with any other genes or gene products to ameliorate or worsen other conditions?

Specific Research Priorities:

1. Population-based studies of sickle cell trait using existing databases and biorepository samples.
2. Prospective studies for exertion-associated genetic associations.
3. Cohort studies of athletes with exertion-related symptoms and evidence-based interventions.