Dr. Arkasubhra Ghosh
Director, GROW Research Lab, Sr. Principal Investigator arkasubhra@narayananethralaya.com+91-80-6666-0660/0712
Curriculum Vitae
Over the past several years since my foray into basic molecular research, I have had the opportunity to work on plant microbes, yeast, mammalian cells, mouse and dog models before beginning discovery research in human diseases. I developed a keen interest in discovery of genetic and signal transduction networks in various human diseases for which our team uses large scale platforms such as proteomics, biomarker screening and sequencing. During 2012-2013, I set up the research wing within the teaching hospital Narayana Netralaya, where collaboration with clinicians is paramount. My research interests focus on novel discoveries from patient samples which point to the underlying genetic and cellular signalling networks associated with human diseases. My goal is to develop clinically relevant biomarkers of disease as well as targeted therapies including AAV mediated gene therapy for both inherited and acquired diseases. As PI and co-PI, I am involved in multiple funded projects that involve the analysis of inflammatory, autophagic and metabolic signalling networks in ocular diseases, muscle diseases and cancers with collaborators within India and internationally. As part of these projects I am actively involved in mentoring graduate scholars, clinical fellows and post doctoral fellows.
1. Gene Therapy: Development of novel recombinant Adeno-associated viral vector strategies:
interests in gene therapy focus on the usage of AAV (Adeno-associated virus) vectors for the treatment of human diseases. On the disease front we have funded studies to develop gene therapy for
- Inherited retinal diseases, LCA (mutation dependent and independent strategies), Retinitis Pigmentosa and Stargardt disease.
- Age-related macular dystrophy
- Keratoconus and corneal wound healing
- Muscular Dystrophy: DMD, GNE myopathy, LGMD
- Sickle Cell Anemia
- Inherited encephalopathy
In order to develop gene therapy vectors we focus on transgene modifications, promoter specificity and optimisation for efficient expression. We are also studying various capsid modifications and working with many capsid mutants to improve overall gene transduction. While developing AAV vectors for these conditions, I also interact with the patient advocacy groups, the clinical teams and regulatory bodies to help advance gene therapy in India.
2. AAV dual vectors:
We have a keen interest in developing recombinant AAV vector modalities for large transgenes utilising novel split gene strategies (10.1089/hum.2010.122; 10.1038/sj.mt.6300322). We have developed and improved strategies of gene delivery to muscle, heart, eye and subsequently throughout the body in mouse and dog models (10.1038/sj.mt.6300081) previously. These novel split gene vectors resulted in 2 patent applications, of which 1 was converted to a full patent (US 2010/0003218 A1) which has been licensed in the USA for a clinical trial. Now, we have developed new gene therapy strategies that utilize alternate hybrid dual vector strategies. These new modalities have now been evaluated in ocular and muscle gene therapy strategies as part of our ongoing studies.
3. AAV vector production strategies for clinical applications:
We are now in preparation for initiation of human clinical trials across a number of ocular and non-ocular conditions. To achieve that we have a class100/class A clean room facility that is equipped with bioreactors and various filtration and chromatography tools for rAAV purification. The research in AAV production and purification strategies are focused on improving yield and quality of the vectors to lay out a blueprint of efficient AAV production to reduce the cost of the final product.
4. Identification of disease-specific molecular biomarkers and cellular profiles in ocular conditions:
Over the past decade, we have extensively worked on cataloging disease severity and treatment response based biomarkers from patient samples such as tears, aqueous humor, vitreous humor, blood/serum, tissues and ocular surface wash samples. These discoveries are now being applied to point-of-care diagnostic test development for clinical deployment. We continue to study and discover biomarkers using multiplex ELISA, proteomics, metabolomics and sequencing tools.
5. Research in ocular surface diseases:
Ocular surface diseases are a major research area for our group which works in close partnership with the cornea clinical translation team led by Dr. Rohit Shetty. By identifying molecular pathways underlying ocular surface diseases such as Keratoconjunctivitis Sicca, ocular surface inflammation, corneal wound healing, etc., we are involved in developing targeted therapies, some of which are in clinical use today.
A. Keratoconus: We study the molecular mechanisms of Keratoconus in depth using a variety of tools – biomarker analysis in patient tears, patient corneal epithelium and correlation with clinical and imaging parameters. We further model disease associated pathologic molecular processes using in vitro models of inflammation, oxidative stress, ECM modulation and autophagy. Our research has demonstrated the role of chronic inflammation in driving the dysregulated stromal structure and disease progression. We have also recently developed induced pathology animal models to study the roles of these various disease mechanisms. We are now developing topical eye drop based medications for treatment of Keratoconus.
B. Dry Eye Disease: The DED research has focused on the identification of the molecular milieu in patient tears under various conditions of DED. We have developed a variety of in vitro models including hyperosmolarity, desiccation and inflammatory stress in human corneal cells for evaluating various treatment modalities of DED. As such we actively collaborate with various industry partners for the development of new DED eye drop formulations. Our research led to the launch of autophagy modulators as eye drops for treatment of DED in India.
C. Corneal wound healing: We are interested in understanding the molecular mechanisms of corneal wound healing. We have discovered novel genes such as PREX-1 that can predispose individuals to develop corneal haze post refractive surgery. We also collaborate actively with the Mohan lab at the University of Missouri to develop new modalities such as epigenetic drugs that control ECM remodelling for treatment of corneal scars.
6. Discovery of novel molecular mechanisms in retinal diseases:
Using large scale and targeted discovery platforms, we have identified unique mechanisms across numerous retinal diseases.
A. Retinoblastoma: Retinoblastoma is an eye tumor that afflicts children below the age of five. Over the past several years, we have discovered a number of molecular pathways that are unique in Rb tumors and developed models to study the same. For example, we have identified a new metabolic reprogramming circuit in the pediatric eye cancer Retinoblastoma that can potentially be targeted for treatment using existing drugs.
B. Diabetic Retinopathy: Using targeted immune factor analysis platform on aqueous humor samples, we discovered a set of biomarkers that can potentially identify early diabetic retinopathy, resistance to ocular anti-VEGF therapy. In collaboration with the Sinha lab at the University of Pittsburgh we demonstrated the role of autophagy dysregulation in Diabetic retinopathy. We also show inflammasome activation and expression of inflammatory proteins in diabetic retinopathy in collaboration with the Chaurasia lab at the Medical Center of Wisconsin.
C. AMD (age related macular degeneration): Using a variety of discovery strategies in human samples, we have identified diagnostic/prognostic biomarkers and drug targets in age-related macular degeneration. In AMD, we made the discovery that neutrophils can infiltrate the human eye and drive pathologic inflammatory processes in the retina in collaboration with the Sinha lab at Univ. of Pittsburgh. We also have an interest in understanding the role of telomerase in AMD.
7. Genetics:
We have a keen interest in understanding the genetics of ocular diseases such as Keratoconus, Retinoblastoma, Stargardt disease, Bestrophinopathy, LCA, Diabetic retinopathy and AMD. To that end we have collaborative studies ongoing that have led to the discovery of new genotype-phenotype relationships as well as novel mutations and genes. Our research group has been a contributing member to the mapping of a representative Asian genome. We also contributed to the Glaucoma genetics consortium that discovered new loci in different types of glaucoma.
Publications: PUBMED- Arkasubhra Ghosh
Research Funding:
India Alliance – DBT Wellcome Trust
Indian Council for Medical Research (Govt. of India),
DST-MOTA, The department of science and technology and Ministry of Tribal Affairs
Science and Engineering Research Board (SERB), Department of Science and Technology (Govt. Of India),
Indo-Swiss Joint Research Programme (SNSF-DST, Govt. Of India),
Department of Biotechnology (DBT, Govt. of India),
Vision Group in Science and Technology (Govt. of Karnataka),
Cleft Children International, Switzerland.
Uditi Foundation (New Delhi); WWGM (GNE Myopathy), New Delhi, PPMD (Parent Project on Muscular Dystrophy), Mumbai;
Industry funding
Research Collaborations:
University of Pittsburgh (USA), Singapore Eye Research Institute (Singapore), Univ. of Missouri-Columbia (USA), Medical College of Wisconsin (USA), Maastricht University Medical Center (Netherlands), New York University (USA), Univ. of Minnesota (USA), Univ. of Basel (Switzerland), Indian Institute of Technology –Kanpur (India), IGIB, New Delhi (India), LVPEI, Hyderabad, Vellore Institute of Technology (India), Tezpur University (India), etc.