What about gene therapy?

The ideal cure for thalassemia would be to selectively correct the faulty gene in the relevant cell type in a safe, effective and affordable way. However, 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 gene therapy (GT) is that the same hematopietic stem cell (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 myeloablative drugs are generally administered. The lack of immunosuppression and of graft versus host reactions are the primary reasons why GT is potentially more tolerable compared to BMT and can be potentially applied to any patient at any 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.
It should also be borne in mind that BMT has been done in over 4.000 thalassemic individuals while GT has only been tested in a handful of patients with still little follow up. Many uncertainties remain in terms of long-term safety and efficacy. Also GT seems to still struggle to induce full transfusion-independence in the most common type (β0/β0) of severe thalassemia. Lastly, GT protocols are incorporating increasingly aggressive drugs to get rid of the diseased marrow which may compromise fertility.
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.

These answers have been prepared by:
- Dr. Lawrence Faulkner, Cure2Children medical team coordinator
- Dr. Sadaf Khalid, Cure2Children Pakistan branch coordinator