Prabha Sampath

Trained at the Lerner Research Institute, Cleveland Clinic Foundation in United States, Dr. Prabha Sampath studied gene regulation during inflammation. As a postdoctoral fellow at the Center for Cardiovascular and Regenerative Medicine, University of Washington, Dr. Sampath worked on translational control mechanisms in embryonic stem cell differentiation. Her innovative work is well recognized as evidenced by outstanding publications and multiple awards. Dr. Sampath is the recipient of prestigious A*STAR Investigatorship award and she joined the Institute of Medical Biology, Singapore to set up her own research group in May 2008. She is now a Senior Principal Investigator at the Skin Research Institute of Singapore, holds an adjunct position at the Programme in Cancer and Stem Cell Biology (CSCB), Duke-NUS School of Medicine. She is currently pursuing research on molecular mechanisms underlying dysregulated translational regulation in pro-inflammatory skin disorders. Visualizing these interactions at the molecular level and integrating this information within the framework of pathophysiology Dr. Sampath’s projects are focused on identification of specific novel therapeutic targets.

Design and development of RNAi-based Topical Formulation to Treat Chronic Diabetic Foot Ulcers

Diabetic foot ulcers (DFUs) are devastating complications of diabetes; one in four diabetics develop a non-healing chronic foot ulcer, which potentially leads to lower limb amputation. This globally escalating medical issue lacks approved pharmacologic options. We discovered persistent and aberrant expression of an anti-migratory small non-coding microRNA, miR-198, in the microenvironment of chronic wounds, which prevents keratinocyte migration, re-epithelialization, and wound healing (Sundaram et.al, Nature 2013). Overall, the ability of this tiny molecular rheostat to regulate the expression of an entire cohort of functionally related genes, makes this an attractive drug target for chronic wounds. Our objective is to target anti-migratory miR-198, in chronic DFUs. With the deployment of an integrated miRNA therapeutics approach, we designed sequence-specific antagomiR oligonucleotides (AMOs-198). This, coupled with a judicious combination of chemical modifications will enhance cellular uptake, target specificity, and metabolic stability of AMOs-198 to effectively target miR-198. Cell-penetrating-peptides (CPP), which form non-covalent complexes with AMOs-198, facilitate effective delivery of these oligomers. With the depletion of anti-migratory miR-198, we observed the restoration of all pro-migratory targets of miR-198, which promote effective migration of keratinocytes towards the wound edge, leading to wound closure. The efficacy of these highly specific and non-toxic AMOs-198/CPP complex was further validated by in-vitro and 3D-ex-vivo de-epidermized dermis (DED) and human organ culture model systems. We envisage the development of the first-in-class, early intervention therapeutic to accelerate healing of DFUs, mitigate complications and prevent lower extremity amputations.

Beyond its role in maintaining skin barrier function, miR-335 intrinsically regulates the inflammatory response in the epidermal keratinocytes. The absence of miR-335 in AD perpetuates the expression of a pro-inflammatory target, CASP7, which, in turn, upregulates chemokines. This cascade enhances immune cell recruitment, including monocytes and T cell subsets, amplifying the inflammatory milieu and exacerbating AD pathology. Since miR-335 expression is regulated by histone deacetylases (HDACs), we identified a selective HDAC inhibitor, Belinostat, capable of restoring miR-335 levels, repair the barrier defect and significantly reduce pro-inflammatory cytokines. Topical application of Belinostat in an AD mouse model effectively restored miR-335 expression and attenuated key aspects of the AD phenotype, including skin barrier dysfunction and inflammation. Given that both barrier impairment and inflammation are interdependent drivers of AD, we propose that Belinostat, a small-molecule modulator of miR-335, may offer a dual-action therapeutic strategy that can resolve both, the barrier defect and chronic inflammation in AD, providing a potentially transformative approach for long-term disease management.