Meet the Authors: Dr. Akshay Sharma, MBBS, MSc, and Dr. María Cancio,MD—‘Gene Therapy for Sickle Cell Disease: Practice Recommendations From ASTC and the International Society for Cell & Gene Therapy'

Akshay Sharma, MD, MBBS, MSc, and María Cancio, MD, are the authors of “Gene Therapy for Sickle Cell Disease: Practice Recommendations From the American Society for Transplantation and Cellular Therapy and the International Society for Cell & Gene Therapy.” They share in this Q&A background on how this research came about, findings that particularly surprised them, and how these findings are guiding current and future initiatives.

Read on for this perspective, and then visit Transplantation and Cellular Therapy, the official journal of ASTCT, for the full article.

Nucleus: What does the recent approval of gene therapies for sickle cell disease represent for patients and the broader field of cellular and gene therapy?

Akshay Sharma, MD, MBBS, MSc and María Cancio, MD (AS/MC): The clinical availability of gene therapy for patients with sickle cell disease has transformed a long-standing dream into reality and represents a landmark achievement for both patients and the clinicians, scientists, and research teams who have dedicated decades to advancing the field through basic, translational, and clinical research.

For patients, it marks the first time a potentially curative therapy can be achieved through the modification of their own hematopoietic stem cells, eliminating the need for a suitable donor and avoiding the risk of graft-versus-host disease (GVHD) associated with allogeneic transplantation.

Gene therapy offers the promise of durable freedom from vaso-occlusive events, a potential reduction in progressive organ damage, improved quality of life, and the opportunity for a future no longer defined by the chronic complications and uncertainty of sickle cell disease. These approvals validate decades of innovation in stem cell transplantation, gene transfer, and gene-editing technologies.

Nucleus: What were the key motivations behind developing this consensus document, and what gaps in clinical guidance does it aim to address?

AS/MC: The primary motivation for developing this consensus document was to address the growing need for practical, evidence-informed guidance in a rapidly evolving field. As curative therapies for sickle cell disease continue to expand, an increasing number of centers worldwide are establishing transplant and gene therapy programs and are being asked increasingly complex questions by patients and families. While expertise has traditionally been concentrated in a limited number of specialized centers, there is a pressing need for pragmatic recommendations that can be broadly disseminated and implemented across diverse clinical settings.

In addition, the landscape has evolved significantly following Food and Drug Administration approval of gene therapy for sickle cell disease. As these therapies transition from clinical trials into routine clinical practice, real-world experience is rapidly accumulating, bringing new insights and new challenges related to patient selection, counseling, toxicity management, fertility preservation, long-term monitoring, and access to care. Clinicians are often faced with questions that extend beyond the scope of existing trial data and published guidelines.

This document aims to bridge these gaps by providing a consensus-based framework that integrates available evidence with expert experience to support clinicians in patient evaluation, counseling, treatment planning, and long-term follow-up. Ultimately, the goal is to promote consistency in care, facilitate informed decision-making, and expand equitable access to these transformative therapies for individuals living with sickle cell disease.

Nucleus: How should clinicians approach patient selection for ex-vivo gene therapy, and what factors are most critical in determining eligibility?

AS/MC: All patients with sickle cell disease should have access to consultation with a specialist in transplantation and cellular therapies to ensure they receive comprehensive information about all available curative treatment options. Education and shared decision-making are essential components of the evaluation process.

Patient selection for ex-vivo gene therapy should be individualized and based on a thorough assessment of the patient's disease severity, medical history, organ function, prior treatment response, psychosocial factors, and personal goals and preferences.

The determination of eligibility requires careful consideration of the risks and benefits of each therapeutic approach, including continued disease-modifying therapy, allogeneic hematopoietic stem cell transplantation, and gene therapy. Factors such as the burden of disease-related complications, quality of life, availability of a suitable donor, fertility considerations, treatment-related toxicities, and the patient's tolerance for uncertainty regarding long-term outcomes should all be incorporated into the decision-making process.

Ultimately, the optimal therapy is one that aligns clinical appropriateness with the individual patient's values, priorities, and expectations.

Nucleus: What are the main challenges associated with stem cell mobilization, collection, and manufacturing in this patient population?

AS/MC: The process requires significant patient commitment and coordination, often beginning with months of preparation, including surgical lines, regular red cell exchange transfusions to optimize hemoglobin S levels and reduce the risk of complications during mobilization and collection.

Mobilization itself can be challenging, particularly in older patients or those with more severe disease manifestations and ongoing symptoms. Achieving adequate stem cell yields may require multiple collection sessions, and in some cases, adjustments to the mobilization strategy or mobilizing agent. Many patients also require placement of a central venous catheter to facilitate apheresis. Beyond collection, manufacturing introduces additional complexities, including variability in product quality and potential cell loss during processing, which can affect the final therapeutic product.

Importantly, stem cell collection is only one component of a much longer treatment journey. Patients must subsequently undergo myeloablative conditioning and hospitalization, with close monitoring and management of chemotherapy-related toxicities and potential complications associated with the gene therapy product.

Successful treatment depends not only on technical aspects of mobilization and manufacturing, but also on multidisciplinary coordination, patient engagement, and the ability to safely navigate each step of this complex process.