It is estimated that 72 to 96 million Indians suffer from rare genetic disorders. Most of these disorders are monogenic and occur due to loss-of-function mutations in the disease-causing gene. In addition, various cancers and metabolic disorders occur as a result of loss of protein function. For few genetic disorders and cancer, intravenous injection of therapeutic proteins is a standard and effective therapy.

However, the cost of therapeutic proteins or enzyme-replacement therapy remains prohibitively high for more than 90% of the global population. For India and other low- and middle-income countries, the cost of such therapies often exceeds the capacity of a family to afford them. Given the lack of cost-effective therapeutics for most rare genetic diseases, it is pertinent to invest our knowledge and resources to address the unmet needs of patients in the Indian context. Urgent focus areas include point of care production of therapeutics to reduce cost and/or innovation in R&D for a quick transition from lab to clinically treating RGD patients.

We are setting up therapeutic interventions against select rare genetic disorders using cutting-edge technology at TIGS, including repurposing small molecule drugs as well as mRNA-based therapeutics and stem cell-based therapies.

Runa Hamid, Vasanth Thamodaran

Spinal muscular atrophy (SMA) is a rare autosomal recessive genetic disorder with an incidence of 1 in 6,000 to 1 in 10,000 live births in the U.S and about 1 in 3900 to 16,000 live births in Europe. Although the incidence of SMA in India is not determined, a carrier frequency of 1 in 38 has been reported from a study conducted in Uttar Pradesh and neighbouring states. Based on this report, and the prevalence of consanguineous marriages, the incidence of SMA in India is speculated to be higher than in US and Europe.

Deleterious mutations in the survival motor neuron 1 (SMN1) gene causes a degeneration of motor neurons, leading to muscle weakness and atrophy. SMN2 gene, an isoform of SMN1 gene is not able to complement the defect due to exclusion of exon 7 during splicing, resulting in truncated non-functional protein expression. Individuals heterozygous for missing or defective SMN1 gene do not exhibit any symptoms of the disease and can therefore act as carriers.

Mortality and/or morbidity is inversely related to the age of onset of disease. The median survival is 7 months, with 95% chances of mortality for children afflicted with Type I SMA. This project has been designed for the development of indigenous small molecule analogues of Evrysdi as oral therapy for SMA. We are working to identify analogues for the existing splicing modulators of SMN2 to bring down the cost of treatment. 13 compounds that are intermediates of Evrysdi have already been synthesized. To validate the ability of the analogues to promote SMN2 splicing, a cellular assay involving luciferase activity and assessing an increase in full length SMN by RTPCR will be utilized. The SMN2-luciferase construct has been generated and expression of luciferase has been validated by transient transfection. We have also optimized an RT-PCR approach to detect increase in the levels of full length SMN transcript.

Investigator: Vasanth Thamodaran

India has one of the highest occurrences of genetic disorders that affect adult β-haemoglobin production (β-thalassemia) or its functionality (sickle cell anaemia). In recent times, gene editing based strategies have been found to be a safe and effective alternative to lentivirus-based gene therapy. Gene editing for treating hemoglobinopathies either involves reactivating foetal haemoglobin expression or correcting the defective β-haemoglobin. Both these strategies have been found to be successful in clinical trials.

In the Indian context, CRISPR-Cas9 based gene editing approach to treat hemoglobinopathies has been well studied. However, the therapy can cost up to 50 lakhs INR, making this life saving treatment less accessible. We are working on different components in gene editing based gene therapy, where identifying alternative strategies can cut down cost.

Investigator: Vasanth Thamodaran

Spinocerebellar Ataxia-12 (SCA-12) is an autosomal-dominant rare genetic disorder caused by the abnormal expansion of CAG repeats in 5’UTR of PPP2R2B gene. The underlying cause of the pathogenesis is not known but it may be due to abnormal regulation of PPP2R2B expression due to CAG expansion. The hypothesis is that an animal model which has PPP2R2B homolog should exhibit SCA-12 behavioural and quantitative phenotypes upon inserting CAG tandem repeats in 5’UTR. This model can be used for the drug screening. With this aim we are developing a humanised PPP2R2B Drosophila model which has twins (tws) as homolog.

The aim of the project is to develop a Drosophila model for SCA-12 disorder having tandem CAG repeats in the regulatory region of PPP2R2B gene

  • To insert different lengths of CAG repeats in regulatory region of twins (tws) gene (Drosophila homolog of human PPP2R2B)
  • To generate a humanised model by inserting PPP2R2B with CAG repeats in 5’UTR

Investigator: Runa Hamid

Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR), Bengaluru