Curing thalassemia: How does bone marrow transplantation compare to gene therapy?

Dr. Lawrence Faulkner. Director Sankalp-People Tree Hospitals Bone Marrow Transplant Unit, Bangalore, India and Medical Coordinator Cure2Children Foundation Florence, Italy. The ideal cure for thalassemia, or for any other genetic disorder, would be to selectively correct the faulty gene in the relevant cell type in a safe, effective and affordable way. In the case of severe thalassemia this cell is the so called hematopoietic stem cell (HSC), the cell that has the unique ability to both give rise to all blood cells and at the same time to self-renew so that this vital cell production is maintained throughout life. This HSC resides primarily in the bone marrow. Gene therapy (GT) aims at incorporating a functional hemoglobin gene into the patient’s own HSC while bone marrow transplantation (BMT) replaces the abnormal thalassemic HSC with that of a healthy donor. Of course there are huge implications for this apparently simple difference: BMT faces the problem that donor cells tend to be rejected if not compatible (matched for Human Leukocyte Antigens or HLA), moreover, even if HLA-compatible, there are so called minor histocompatibilty antigens (outside the HLA system) which can still induce HSC rejection. To prevent this, drugs which suppress the immune system are required resulting in increased risks of infections and other problems. On the other hand it is quite difficult to incorporate a new functional gene in any cell type, and adequate hemoglobin production requires a particularly active gene. The advantage of GT is that the same HSC of the patient is used and thus immunosuppression is not required, in fact, the patient’s own bone marrow is collected and incubated with viral vectors capable of “infecting” the stem cell with the missing normal hemoglobin gene. This corrected autologous bone marrow is than infused back into the patient after the administration of drugs capable of reducing the amount of defective thalassemic marrow, so called myeloablative drugs, similarly to what is also used for BMT. In BMT however myeloablative drugs are combined with immunosuppressive drugs while in GT only a milder dose of myeloabloative drugs are generally administered. This is primarily why GT is potentially more tolerable compared to BMT. In addition, GT can be potentially applied to any patient at any age while BMT requires a compatible donor and it’s toxicity currently limits it’s use to younger patients, generally less than 15 years of age. However, BMT strategies are improving in parallel with GT so that is is increasingly possible to transplant between partially compatible individuals and older thalassemics. Last but not least the issue of cost and accessibility: BMT cost can vary between 8 to 40 lakhs INR depending on available donor type, while at present GT technology and regulatory issues make it quite expensive so that the preparation of gene-corrected marrow is currently costing in the range of 7 crores INR. Another major difference is that since its beginning, in 1980, BMT has been done in over 4.000 thalassemic individuals and long-term follow up studies suggest that it can restore an essentially normal health-related quality of life1, while GT has only been tested in a handful of patients with still little follow up so that many uncertainties remain in terms of long-term safety and afficacy. While BMT effectively results in transfusion independency in the great majority of patients (>80%)2, GT seems to still struggle to induce full transfusion-independency in the most common type (β0/β0) of severe thalassemia. In conclusion, BMT and GT have many similarities and are both evolving into increasingly effective, safe and widely applicable therapies. GT is still in its early stages and results are not yet satisfactory, particularly for the most severe forms of thalassemia, let alone cost and regulatory issues. At present most young children with a compatible donor are expected to do very well with BMT and waiting for GT might not be justified, while for older patients or those lacking a compatible donor it is more difficult to provide sound recommendations. References 1. La Nasa G. et al. Long-Term Health-Related Quality of Life Evaluated More than 20 Years after Hematopoietic Stem Cell Transplantation for Thalassemia. Blood 122: 2262–70, 2013. doi:10.1182/blood-2013-05-502658. 2. Angelucci E et al. Hematopoietic Stem Cell Transplantation in Thalassemia Major and Sickle Cell Disease: Indications and Management Recommendations from an International Expert Panel.” Haematologica 99:811–20, 2014. doi:10.3324/haematol.2013.099747. 3. M.C. Walters et al. Update of Results from the Northstar Study (HGB-204): A Phase 1/2 Study of Gene Therapy for Beta-Thalassemia Major Via Transplantation of Autologous Hematopoietic Stem Cells Transduced Ex-Vivo with a Lentiviral Beta AT87Q-Globin Vector (LentiGlobin BB305 Drug Product),. Abstract 201, 2015 Annual meeting of the American Society of Hematology. available at https://ash.confex.com/ash/2015/webprogram/Paper78466.html