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Getting to Cure: Gene Therapy for Sickle Cell Disease

December 12, 2023
Hilary Whitworth, MD, MSCE, (@HilaryWhitworth)
Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA

The gene therapy and sickle cell disease communities are buzzing about two new products: lovotibeglogene autotemcel (lovo-cel) and exagamglogene autotemcel (exa-cel), just approved by the Food and Drug Administration (FDA) on December 8! Updates on both products were highlighted in the yesterday’s session, Gene Therapies: The Long and the Short of Clinical Trials in Blood Disorders. The abstract Efficacy, Safety, and Health-Related Quality of Life (HRQOL) in Patients with Sickle Cell Disease (SCD) Who Have Received Lovotibeglogene Autotemcel (Lovo-cel) Gene Therapy: Up to 60 Months of Follow-up was presented by Julie Kanter, MD, and “Exagamglogene Autotemcel for Severe Sickle Cell Disease” was presented by Haydar Frangoul, MD. 

Dr. Kanter presented updated data on the lentiviral vector product, lovo-cel, which encodes for a modified β𝛽-globin gene, producing an anti-sickling hemoglobin (HbAT87Q). According to the data, 90.9% of evaluable participants experienced complete resolution of vaso-occlusive events, and those with evaluable health-related quality of life (HRQOL) scores reported improvements in pain intensity, pain interference, and fatigue. The authors described adverse events, including those reflecting known side effects of autologous hematopoietic stem cell transplantation with myeloablative conditioning, such as stomatitis and thrombocytopenia, as well as myelodysplastic syndrome diagnosed in one participant. Next, Dr. Frangoul presented the data on exa-cel, a CRISPR-Cas9 gene editing approach that increases fetal hemoglobin. Dr. Frangoul and co-authors reported that 95% of evaluable participants remained free from vaso-occlusive events at 12 months and beyond, and quality of life measures also exhibited improvement from baseline. Adverse events were reportedly similar to known side effects of myeloablative conditioning including stomatitis, nausea, febrile neutropenia, headache, and vomiting, with one death due to COVID-19 respiratory failure, which was unrelated to exa-cel treatment. 

I had the pleasure of speaking to former ASH president Alexis Thompson, MD, hematology division chief at the Children’s Hospital of Philadelphia, and an expert in sickle cell disease and gene therapy, about this exciting time. Dr. Thompson acknowledged that there is likely insufficient knowledge among patients and providers about gene therapy, and that we need more opportunities to disseminate practical information about these new products. Early conversations with a trusted provider will be the first step in a patient’s gene therapy journey, which Dr. Thompson said will be critical. 

“Conversations beginning in the clinic of their primary hematologist or sickle cell center allow patients to be sure they come to their gene therapy or transplant appointments with questions in hand,” she shared. We discussed that, while many patients and providers will be focused on eliminating sickle cell disease, it is important to consider all patient values and priorities when considering the risks, including fertility and options for fertility preservation. “Safety is a key consideration for the sickle cell disease population … it is important to articulate clearly the likelihood of success and the risks associated,” she said, adding that “it may take some people months to make these decisions.”  

Her comments underscored how important it is to be prepared for the implementation of these products, including the ability to counsel patients and families about the products, risks, and alternatives. Thankfully, a few of the abstracts this year hit on this crucial topic. Steven J. Hardy, PhD, presented the abstract “Assessing Psychosocial Readiness for Gene Therapy in Sickle Cell Disease: A Consensus Statement” in the Saturday session Health Services and Quality Improvement – Non-Malignant Conditions: Access to Quality Care in Classical Hematology. Dr. Hardy shared consensus recommendations from the National Heart, Lung, and Blood Institute’s Cure Sickle Cell Initiative (CureSCi) Patient Readiness and Resilience Working Group, which includes representative perspectives from patients, advocates, clinicians, and researchers. The group developed four domains for guidance including education delivery and evaluations of knowledge, interest and motivation, and psychosocial risk and resilience. Any clinician planning to administer gene therapy for sickle cell disease should learn about these consensus recommendations and familiarize themselves with the complex process of readying a patient and an institution for this potentially life-changing therapy.  

In the same session, Ashish O. Gupta MBBS, MPH, presented “A Collaborative Model for Improving Patient Engagement and Access for Hematopoietic Stem Cell Transplant and Clinical Gene Therapy Trials for Patients with Sickle Cell Disease in the Upper Midwest United States.” Dr. Gupta highlighted the efforts of hematology and transplant teams at six institutions in the Midwest that have implemented a model for providing comprehensive care and a smooth referral system for patients and families interested in transplant and gene therapy. Clinicians can learn from this experience and leverage these collaborations when providing gene therapy products as they become clinically available.  

These sickle cell disease gene therapy studies provide hope for a future in which patients have multiple options for curative therapy and in which clinicians are prepared to deliver this kind of care. We have a long way to go, but this inspiring lineup of abstracts will surely motivate the field to keep moving toward a cure for all patients.  

Dr. Whitworth indicated no relevant conflicts of interest.   


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