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DBT’s programme for developing treatment for sickle cell disease

Sickle cell anaemia is a hereditary disease, predominantly seen amongst tribal populations. In the country, about 1.8 Crore (18 million) people carry the sickle cell trait and 14 lakh (140,000) suffer from sickle cell disease.This disease is caused by a point mutation at codon 6 of the human beta-globin gene with the result that glutamate is replaced by valine in the protein, resulting in genetically abnormal haemoglobin (Hb) structure. Those with the sickle-cell trait have one normal HbA allele and one abnormal HbS allele, whereas affected individuals have both abnormal HbS alleles. If both the parents are the carriers, then there is a 25% chance of producing an affected offspring. Patients suffering from this disease have sickle-shaped red blood cells. The disease is manifested as hemolysis, microvascular occlusion, tissue damage, etc.

Currently, human leukocyte antigens (HLA) matched haematopoietic stem cell transplantation (HSCT) is the only way to treat this disease. But this method has its limitations, as most patients do not get a matched sibling donor and transplants from unrelated donors have higher risks of complications, owing to immune reactions between the donor and the recipient.

Since allogeneic HSCT has its limitations, a patient’s own bone marrow stem cells, i.e., autologous haematopoietic stem cells (HSCs) can be used for transplantation. The defective gene responsible for sickle cell disease in autologous HSCs can in principle be replaced with a normal gene using genome-editing techniques (ZFN/TALEN/CRISPR) or through expression of beta globin gene using lentiviral vectors. Disease free HSCs then can be transplanted back in to the patient. These gene-editing and gene-therapy approaches require stringent safety and ethical clearances for trial. The research itself is at early stages, so trials need to begin and progress.

A similar approach of gene therapy can, in principle be applied to patient-derived induced pluripotent stem cells (iPSCs) which can be generated through re-programming (using a set of transcription factors) of the somatic cells taken from the patient suffering from sickle cell disease. The defective gene can be corrected using genome editing techniques. These iPSCs can further be differentiated into HSCs and then transplanted. Such studies are even further away and pose great challenges.

The long-term goals of researchers in DBT’s programme include exploring the potential of stem cell technology for developing treatment for sickle cell disease. An appropriate regulatory framework for conducting clinical trials in this area is being formulated by the Government.

For the current management of this disease, coordinated efforts are being made at several fronts in an integrated manner. The Ministry of Tribal Affairs (MoTAs), Department of Health (DHR), Ministry of Health and Family Welfare (MoHF&W) are working together for awareness programmes by conducting training and workshops; screening; and counselling. The DBT took the initiative during the 1990s and established genetic counselling units in hospitals for screening of groups suffering from various genetic disorders, including sickle cell disease. Now, the DBT is working with the MoTAs, DHR, MoH&FW for scaling-up of existing programmes for management of sickle cell disease.

Though some of the State Governments have taken initiatives, Gujarat is at an advanced stage and has developed a model where its Department of Health, Department of Tribal Affairs, Indian Institute of Public Health, Gandhinagar, and Indian Red Cross Society, Gandhinagar are working together for management of this disease. Efforts are being made to scale-up activities in the State and also to replicate the model in other States. The stakeholders are working together to prepare a “Coordinated Action Plan” in this area.

Input by: Dr. Alka Sharma