Akshay Sharma, MBBS, on Overcoming Challenges for Administration of Ex-Vivo SCD Gene Therapy

“Hopefully, in the next 5 to 10 years, we will have figured out all these things: how to mobilize cells better and how to give cells with lesser toxicity. I think all of these things will improve the safety profile of gene therapy for patients with SCD.”

On December 8, 2023, the FDA approved Vertex Pharmaceuticals' and CRISPR Therapeutics’ exagamglogene autotemcel (exa-cel, marketed as Casgevy) and bluebird bio’s lovotibeglogene autotemcel (lovo-cel, marketed as Lyfgenia) for the treatment of sickle cell disease (SCD). Both exa-cel and lovo-cel are ex-vivo autologous gene therapies, and are manufactured and administered in a multistep process. Patients first need to receive an agent, plerixafor, to mobilize their hematopoietic stem cells to the peripheral blood for collection. Collecting an adequate number of cells for manufacture of the gene therapy product can take several days. After the cells are genetically modified outside the body, patients also need to undergo myeloablation to wipe out their unmodified hematopoietic stem cells before they can receive the modified cells. This is accomplished with the use of chemotherapy in the form of busulfan, which carries a number of short-term risks, such as immunosuppression and ulcers, and long-term risks, such as secondary malignancies.

Following his presentation on the new SCD gene therapies at the 2024 Tandem Meetings |Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, held in San Antonio, Texas, February 21-24, 2024, CGTLive® sat down with Akshay Sharma, MBBS, the attending physician and assistant member of bone marrow transplantation and cellular therapy at St Jude Children’s Research Hospital, to learn about further areas of interest for research in the field. Sharma discussed potential alternatives to plerixafor and busulfan that are currently in development for use in the context of SCD gene therapy and expressed hope that some of these may make the gene therapies safer to receive in coming years. He also spoke about the high financial cost of receiving the SCD gene therapies and the need to expand accessibility to the populations that need them most.

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REFERENCES
1. Sharma A, Sheehan V, Shenoy S. Tandem Thursday breakfast symposium: the evolving paradigm of sickle cell disease management. Presented at: 2024 Tandem Meetings, February 21-24, San Antonio, Texas. Session #S-B1.