Research Highlight

Dumpati Srikanth

Dr Indumathi Mariappan, Ph.D

Designation: Research Scientist, Sudhakar & Sreekanth Ravi Stem Cell Biology Laboratory

Dr Indumathi Mariappan completed her doctoral training in the area of Cell Biology and Molecular Biology at the Centre for Cellular and Molecular Biology (CCMB), Hyderabad in the year 2005. She also underwent a three year post-doctoral training at CCMB before joining the Stem Cell Biology Laboratory at LVPEI in 2008. Dr Mariappan’s lab is involved in basic and translational research towards addressing the problems of retinal and corneal diseases using different sources of adult and pluripotent stem cells.

I am currently handling three government funded projects, focused on the applications of patient-specific induced pluripotent stem cells in cell therapeutic applications. My lab is also involved in genome editing work, wherein we attempt to edit some of the disease causing gene mutations in patient-derived stem cells. Such mutation edited stem cell lines can then generate normal ocular cells for autologous cell therapeutic applications. Using the same genome editing approach, we also create mutant models of stem cells and zebra fishes, to understand how various disease causing gene mutations can affect normal cellular functions and tissue development.

The details of the individual projects are listed below.

I. Exploring the application of pluripotent and adult stem cells in the treatment of retinal and corneal disorders.

  • Investigators: Indumathi Mariappan, Vivek Pravin Dave, Subhadra Jalali, Chitra Kannabiran, Virender Singh Sangwan, Tara Prasad Das, Dorairajan Balasubramanian
  • Funding support: Department of Biotechnology, Government of India
  • Objectives: Our group is currently exploring the applications of pluripotent stem cells (PSCs) in the treatment of retinal and corneal disorders. Towards this effort, this project aims to establish efficient protocols to 1. Differentiate pluripotent stem cells into retinal and corneal lineages. 2. Enrich differentiated cells into homogenous populations and three dimentional organoids 3. Evaluate the suitability of PSC derived ocular tissues in treating different retinal and corneal problems in pre-clinical animal models.
  • Significant research outcomes: As a part of this study, we have successfully derived and characterized few patient-specific induced pluripotent stem cells. These iPSCs were then differentiated into retinal and corneal lineages to generate three dimensional neuro-retinal cups and minicorneal organoids. These self-organized miniature organoids can now serve as unlimited tissue sources for regenerating damaged retinal and corneal tissues. Read More

II. Creating zebra fish models of retinal dystrophy using genome editing methods.

  • Investigators: Indumathi Mariappan, Rakesh Mishra*
  • Funding support: Department of Biotechnology, Government of India
  • Objectives: Mutations in several genes involved in phototransduction pathway, vitamin A metabolism, photoreceptor specific transport proteins, transcription and splicing factors are linked to retinal dystrophies. However, the physiological effects of only certain pathogenic mutations are very well understood. This study aims to employ genome editing tools to generate near-identical zebra fish models of human gene mutations implicated in disease and aims to understand their effects on retinal development and function.

III. Proof-of-concept experimentation on gene correction in patient-specific induced pluripotent stem cells by genome editing approach

  • Investigators: Indumathi Mariappan, Chitra Kannabiran, Dorairajan Balasubramanian
  • Funding support: Department of Science & Technology, Government of India
  • Objectives: This project aims to correct the known genetic mutations in retinal dystrophic patient-specific induced pluripotent stem cells. Mutation correction will be attempted either by delivering a normal copy of the mutated gene, at a safe harbor locus in the genome or by editing the mutation in situ using the latest genome editing tools such as the TALEN and CRISPR systems.

We believe that our stem cell work could help in developing newer cell therapeutic applications for the treatment of both genetic and non-genetic diseases such as retinal dystrophy, corneal dystrophy, bilateral limbal stem cell deficiency and others, which do not have a definitive treatment modality right now.

As a part of the ongoing collaborative work between LVPEI (Dr Virender S Sangwan) and Linkoping University, Sweden (Prof. May Griffith), we also hope that that the biosynthetic corneal prosthesis under evaluation would benefit a larger number of blind patients at affordable costs.

Adult stem cell therapy for corneal surface reconstruction has become the gold standard in the current decade, with technical and surgical innovations such as the cultured limbal epithelial transplantation (CLET) and simple limbal epithelial transplantation (SLET). However, the treatment of bilateral defects, corneal endothelial and trabecular meshwork dysfunction, genetic disorders affecting corneal and retinal functions remain a challenge till date. Nevertheless, the advent of somatic cell reprogramming and the possibility of in situ gene editing have raised newer hopes in the recent times. Many research groups around the world are currently exploring these possibilities as alternative modes of disease treatment.

Our research efforts are mainly focused on finding cell therapeutic options for the treatment of various genetic dystrophies affecting the eye. Therefore, allogenic cell therapy with normal functioning cells would be the way forward to cater to the needs of larger masses. This would necessitate the establishment of well characterized cell banks. We also have plans of combining cell therapy and gene therapy to explore the possibility of autologous applications and personalized medicine.

*Dr Rakesh Mishra (Centre for Cellular and Molecular Biology, Hyderabad, India).

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