Parkinson’s disease in a petri Dish: Harnessing iPSCs to develop an improved model of personalized medicine
Parkinson’s disease (PD) is multifactorial and clinically heterogeneous. Recent advances in research in PD increasingly indicate that genes and environmental factors can interact to modulate the risk of disease. Indeed, epidemiological reports suggest distinct differences in gene variants in PD between western and eastern populations. Thus far, differences in PD-related gene variants between East and West have been reported for LRRK2, MAPT, BST1 and PARK16 genes. These differences can cause phenotypic alterations in pathobiologies and drug metabolic pathways, and it is thus crucial that PD treatment strategies take these ethnicity variations into consideration. However, current disease modelling and drug development programs largely use animal models that fail to replicate human ethnicity differences. It is now well-established that humans and mice have considerable developmental, genetic and physiological differences, and that genetic mutations for human PD do not completely replicate the disease phenotype in mice. Therefore, the search for models that mirror patient-specific PD phenotypic manifestations as closely as possible still continues. Patient-derived human induced pluripotent stem cells (iPSCs) can fill this lacuna between genetic association studies and underlying molecular mechanisms. iPSCs can be selectively differentiated into specialized cells of all three lineages, and thus PD patient-specific iPSCs can be used not only to derive dopaminergic neurons but also intestinal cells and microglia which are also known to be affected under certain familial PD conditions. The potential to derive other specialized CNS cells from iPSCs also open the gates to test any drug-induced effect on these cells, and will help to establish specific genetic risk factors to assess genetic sub-populations’ differing responses to treatment. Unlike other artificially-induced models, endogenous cellular machinery and transcriptional feedback are preserved in iPSC models, a fundamental step in accurately modelling this genetically complex disease. The underlying cellular pathogenesis can be accurately traced and modelled using these cells, which also hold the potential for mutations to be genetically corrected and their phenotypic manifestation on the disease pathology evaluated. Thus, iPSC derived cells can be harnessed for developing improved cellular models which will be instrumental in dissecting a complex pathological process into simpler molecular events; in turn a step forward towards personalized medicine in PD.
Dr. Indrani Datta is an Associate Professor of Neuroscience at the Department of Biophysics, NIMHANS, Bengaluru. She completed her M. Phil. and Ph.D. in Biophysics from NIMHANS. She had a short stint thereafter in industry as a Research Scientist in Stempeutics, a Manipal group company involved in stem cell therapeutics. She returned to academia as an Assistant Professor at the Manipal Institute of Regenerative Medicine, Bengaluru. As a founder-faculty of the institute, she was actively involved in the development of the syllabus and course content of the M.Sc, M.Phil and Advanced Diploma courses. In 2014, she joined her alma-mater as an Assistant Professor and Neuroscientist. She was awarded the Innovative Young Biotechnologist Award (IYBA) from the Department of Biotechnology, Govt. of India, in 2014. Earlier in 2010, she had received Fast Track Scheme for Young Scientists from Department of Science and Technology, Government of India. She also serves as the Chairperson of the Institutional Committee for Stem Cell Research (IC-SCR) of Eyestem, CCAMP, Bengaluru and is a member of the Cryosave IC-SCR. She has many International peer-reviewed Pubmed-cited publications as well as book chapters, and is a reviewer for several prestigious international scientific journals. Throughout her career, she has proactively generated funds for her research from government funding agencies like DBT, DST, ICMR and CSIR. One of her current research projects funded by the Biotechnology Industry Research Assistance Council (Entrepreneur Industrial scheme of Govt. of India) is working on generating patient-specific induced pluripotent stem cell lines (iPSCs) from Parkinson’s disease patients of Indian ethnicity, for the first time in the country.