Despite being one of the world’s most common inherited blood disorders, sickle cell disease has few treatment options, even with the approval of three new drugs since 2017. Several companies hope to use new gene-editing tools to cure the disease by targeting the mutations that cause it. One such treatment is in the final stage of human testing and may be submitted for approval in late 2022 or early 2023. While candidates in the pipeline show great promise for a gene-based treatment for sickle cell disease, the challenges facing the practical use of any such innovations may get in the way of changing the global impact of this disease.
In sickle cell disease, the gene that creates hemoglobin is mutated, causing red blood cells to be sickle-shaped, hard, and sticky. They can get stuck in small blood vessels and clog blood flow, causing unpredictable and painful clotting episodes known as vaso-occlusive crises, stroke, and acute chest syndrome, a potentially life-threatening condition that results from sickled cells clogging blood vessels in the lungs. People with two copies of the mutated gene experience more severe symptoms, partially because the affected blood cells die early, contributing to anemia. The estimated median life expectancy for someone with sickle cell disease is 45 to 55 years. Sickle cell disease is a global health issue and most common in Africa, the Middle East, and India. Advances in treatment are slow to reach the populations most affected.
Current FDA-approved treatments targeting disease complications include:
- Hydroxyurea, a pill approved in 1998 for adults and in 2017 for children age two and older
- Endari® (l-glutamine oral powder) from Emmaus Life Sciences approved in 2017 for patients aged five and older
- Adakveo® (crizanlizumab) a monthly infusion from Novartis, approved in 2019
- Oxbryta® (voxelotor) a tablet from Global Blood Therapeutics, approved in 2019
In severe cases, patients may receive blood transfusions as a course of therapy. Bone marrow transplants are an option but come with the risk of fatal side effects.
Potential Benefits of Gene Therapy and Candidates in the Pipeline
Rather than treating the symptoms and complications of sickle cell disease, gene therapy has the potential to dramatically lessen the impact of, or possibly even cure the disease. Treatment could mean reducing or eliminating the need for medications, blood transfusions, and hospitalization for painful clotting episodes.
Gene therapies for sickle cell disease currently in clinical trials include:
- LentiGlobin, from Bluebird Bio, is made by engineering a patient’s stem cells to carry a corrected version of the hemoglobin gene. A small study found that the drug restored hemoglobin levels to normal and almost eliminated vaso-occlusive crises and acute chest syndrome. A Phase 3 study is ongoing.
- CTX001, by CRISPR Therapeutics and Vertex Pharmaceuticals, employs CRISPR-cas9 technology to instruct the stem cells to pump out high levels of fetal hemoglobin, which the body naturally stops producing around six months after birth. Promising results from a small study showed that participants had not experienced vaso-occlusive crises after three months. Two Phase 1 / 2 trials are ongoing.
- OTQ923/HIX763, from partners Novartis and Intellia Therapeutics, are currently recruiting trial participants uses a similar CRISPR-led strategy to CTX001. Novartis and Intellia Therapeutics are currently recruiting trial participants.
- ARU-1801, from Aruvant Sciences, uses genetically modified cells to encode a subunit of fetal hemoglobin and is currently being evaluated in a Phase 1 / 2 study.
- BIVV003, from Sangamo Therapeutics and Bioverativ (a Sanofi subsidiary), also aims to increase fetal hemoglobin via gene Editing. Sangamo Therapeutics and Biovertiv are currently recruiting participants for a Phase 1 /2 trial.
Manufacturing and safety concerns have slowed Bluebird Bio’s LentiGlobin progress. After one study participant developed leukemia and another presented with what was believed to be a bone marrow disease, Bluebird paused the clinical trial. After investigation, the company reported that the therapy was unlikely to have caused the leukemia, and the bone marrow disease was a case of transfusion-dependent anemia. The FDA announced in June that the company could resume the studies.
What may be the main challenge facing genetic treatment for sickle cell disease isn’t reflected in clinical trial settings – it is the real-world complication of equity and access. The highest incidence of sickle cell disease is in sub-Saharan Africa and India, areas where access to healthcare and below-average incomes are prevalent issues. Gene therapies are costly and difficult to produce. This, combined with complexities associated with supply-chain and the need for medical administration will create barriers for areas of the world with the greatest need.
Bluebird, followed by CRISPR and Vertex, appear most likely to seek approval in the next two to three years. Candidates from Aruvant Sciences and Sanofi and Sangamo Therapeutics may be three to five years off. Novartis states they are working to address access and equity issues, but how they plan to tackle those long-standing problems is unclear at this time.
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