Messenger RNAs (mRNAs) are a fast-emerging class of biotherapeutics. mRNA therapies offer a new opportunity for targeted treatment of challenging diseases and flexible manufacturing, as demonstrated by the rapid development of mRNA vaccines against COVID-19. They are non-infectious, non-integrating, and cell-free, offering both rapid and readily scalable production with high productivity. TIGS is specifically focused on the development mRNA-based therapies for Lysosomal storage genetic disorders, Neuromuscular genetic disorders, and Cancer. Our team at TIGS are currently working towards the design & generation of therapeutic mRNAs and developing alternative lipid formulations for improved encapsulation and stability, using specialized devices for encapsulation and high throughput assessment of lipid formulations.
Monogenic rare genetic disorders are a result of loss of protein function. In a few such diseases, intravenous biweekly administration of therapeutic protein has been found to rescue disease symptoms and improve the patient’s life. Though effective to a certain degree, these therapies are costly. This cost is primarily due to the cost intensive purification methods to produce therapeutic proteins. We reasoned that, as an alternative to protein therapy, mRNA encoding therapeutic proteins can be utilized to produce the therapeutic proteins in vivo. mRNA production, owing to its synthetic nature, is highly scalable with a relatively smaller footprint which ultimately leads to affordable therapeutic solution for many diseases. The platform nature of mRNA biotherapeutic technology allows for a plug and play design and by virtue of which, mRNA-based drug can be developed simultaneously for a group of disorders sharing a commonly affected cell type or tissue using a universal production pipeline. mRNA technology holds a future where one can potentially combat rare genetic disorders, infectious disease, and cancer, not as individual challenges, but as one whole altogether.
TIGS has an optimized workflow for the research and development of mRNA based therapeutic candidates and currently preclinically validating multiple mRNA based drug candidates for rare genetic disorders and cancer.
Team
Rajesh V Iyer
Collaborators:
Ashoka University, Sonipat
BRIC – Institute of Stem Cell Science and Regenerative Medicine (inStem), Bengaluru
Indian Council for Medical Research, New Delhi (ICMR)
Indira Gandhi Institute of Child Health (IGICH), Bengaluru
National Centre for Biological Sciences (NCBS), Bengaluru
National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru
World Without GNE Myopathy (WWGM), New Delhi
Activity
Lysosomal storage disorders (LSDs) are a group monogenic rare genetic disorders which occur owing to a loss of lysosomal enzyme function. In LSD patients, intravenous administration of the functional enzyme i.e., enzyme replacement therapy (ERT) has been found to rescue disease symptoms and improve the patient’s life. Though effective to a certain degree, ERT based therapies are very costly. Globally, LSD prevalence is taken to be 1 in 7000-8000 individuals and if extrapolated, there could be more than 1 lakh LSD patients in India. More than 95% of Indian population cannot afford these drugs. This cost is primarily due to the small market size, cost intensive manufacturing and purification methods to produce therapeutic proteins. LSD patients require ERT for their entire life and owing to the absence of any indigenous drugs, only few Indian LSD patients can access these drugs via humanitarian funds. Many succumb to the disease, often due to the unavailability of these drugs.
To address this emergency, we reasoned that, as an alternative to protein therapy, mRNA encoding therapeutic proteins can be utilized to produce the therapeutic proteins in vivo. Using mRNA technology, we have successfully designed therapeutic mRNAs for the treatment of two LSDs; Pompe and Fabry disease. Pompe disease occurs due to the deficiency of acid alpha glucosidase enzyme (GAA) whereas, the Fabry disease happens due to the deficiency of alpha galactosidase enzyme (GLA).
Investigator: Rajesh V Iyer
GNE myopathy is an adult-onset progressive neuromuscular disorder that generally leads to extreme disability in a few years. The disease is caused by mutations in the bifunctional enzyme Glucosamine (UDP-N-Acetyl)-2-Epimerase/N-Acetyl-Mannosamine Kinase involved in sialic acid biosynthesis. There is no approved treatment for this disease.
The aim is to develop mRNA therapy for GNE Myopath. Currently, the mRNA team at TIGS has generated two GNE-encoding mRNA candidates and tested them using cell culture methods. The GNE-mRNA candidates can express in cell lines for more than 4 days and efforts are now on developing muscle targeting nanoparticle formulations.
GNE myopathy is an adult-onset progressive neuromuscular disorder that generally leads to extreme disability in a few years. The disease is caused by mutations in the bifunctional enzyme Glucosamine (UDP-N-Acetyl)-2-Epimerase/N-Acetyl-Mannosamine Kinase involved in sialic acid biosynthesis. There is no approved treatment for this disease.
With the help of the patient advocacy group- World Without GNE Myopathy (WWGM) TIGS is aiming to develop mRNA-based therapy for GNE Myopathy. Currently, the mRNA team at TIGS has generated two GNE-encoding mRNA candidates and tested them using cell culture methods. Efforts are now on developing muscle targeting nanoparticle formulations.
Investigator: Rajesh V Iyer
Neuromuscular genetic disorders (NMGDs) are a set of diseases affecting people of different age-groups, causing extreme disability and loss of life. Duchenne muscular dystrophy is one amongst the prevalent NMGDs and its only available gene therapy-based drug costs 26 crores INR. This therapy is entirely out of the >1million Indian DMD patients.
TIGS serves as the nodal centre for the ICMR (Indian Council of Medical Research, Govt. of India) funded multi-institutional project titled “Centre for advanced research for neuromuscular genetic disorders (CAR-NMGD): Clinical data-based disease modelling, molecular diagnostics, and mRNA based biotherapeutic technology platform”. Under this program, we are developing a preclinically validated mRNA-based gene editing candidate for the treatment of DMD. This approach of in vivo gene editing could enable a single-shot treatment of NMGDs. Additionally, under this program , we are also developing cell, animal, and clinical models for NMGDs. These models would be freely available for aiding India’s drug discovery attempts to find cure for NMGDs.
Investigator: Rajesh V Iyer
Monoclonal antibody therapy dominates the therapeutics protein market for cancer with worldwide sales of nearly $125 billion. However, the cost of antibody therapy still prohibits its equitable access amongst the poor in our country. We are encountering this social issue by developing mRNA-based antibodies for cancer. These mRNA -based antibodies when developed are expected to reduce the cost of monoclonal antibody treatment for cancer by 100 folds.
Investigator: Rajesh V Iyer