Screening for novel drugs is one of the costliest steps in drug development. Modelling rare genetic disorders using Drosophila and cell culture allows for fast, cost-effective screening of novel therapeutic interventions. This also reduces the animal burden in drug development.
We use a cost-effective Drosophila model for screening small molecules, mRNA therapy and anti-sense oligos (ASOs) against less explored diseases and rare genetic disorders. Drosophila shows more than 80% conservation with human genes and pathways. Over the last hundred years, Drosophila researchers have developed excellent genetic tools and behavioural assays useful for testing the effect of drugs and for evaluating their impact on key pathways, behaviours and lifespan.
At TIGS we are developing a model of primary screening in flies, followed by testing of potential candidates in cell culture and animal models. Developing in vitro models using stem cells and induced pluripotent stem cells (iPSCs) provides a ready ‘disease-in-a-dish’ model for studying the effect of interventions on the target cell type. This will make it possible to develop low cost and effective treatments for rare genetic disorders.
The medium used for culturing stem cells is prohibitively expensive with 80% of the cost attributed to cytokines (FLT-3L, SCF, TPO, IL-3, and IL-6). We aim to bring down the cost of cell-based therapy/gene therapy for hemoglobinopathies by in-house production of growth factors required for ex-vivo expansion of hematopoietic stem cells.
We have successfully expressed the growth factors IL3, IL6, SCF, and FLT3L in bacteria, refolded and purified. In addition, three growth factors – IL3, IL6, and SCF – were overexpressed in cytoplasm and purified. The growth factors were also validated using cell lines to check the growth-promoting activity. The validation showed that soluble cytoplasmic growth factors can promote cell proliferation severalfold.
Investigator: Vasanth Thamodaran
We have developed a repository for clinical data on RGDs in the form of a database that can collate and store information of such diseases in the Indian context and focus on the genomic causes and mutations specific to the Indian population. The database includes a wide variety of information related to RGDs from reliable sources. It also includes information on local prevalence, affected genes, pathogenic variants. Clinical data will be sourced from our partner hospitals and research organizations to add patient genetic information to the database.
A web-based platform is developed by incorporating analytical tools for clinical data analysis and interpretive output. Interactive search and query features are built in. Custom programs are in place for automated data extraction and presentation via the user-friendly front-end of the GenTIGS web interface. The browser enables viewing and interactive searching of all the collected information on RGDs and their relevant gene(s), along with structural and functional gene information . We are currently working on incorporating a pipeline at the back end to analyse genome and exome level population data to identify pathogenic variants. In coming days we plan to provide information on patient care services, facilitate pedigree analysis from patient to family and population level using clinical data, which will be a novelty of this database.
The Beta version of GenTIGS is now live! It can be accessed at db.tigs.res.in/gentigs
Investigators: Iliyas Rashid