I016 Felodipine efficiency analysis on induced neurons derived from Huntington’s disease FELL-HD clinical trial patients
Year: 2024
Type: conference-abstract
Abstract: Autophagy, a lysosomal degradation pathway has been shown to be dysfunctional in HD, contributing to insufficient mHTT protein removal. Felodipine (a drug commonly used to treat hypertension) has been shown in pre-clinical models of HD to upregulate autophagy and reduce levels of toxic mHTT with functional benefits. Based on this, the Fell-HD clinical trial was initiated investigating the feasibility and tolerability of this drug in early-stage HD patients. In this project, in parallel with the FELL-HD trial, we tested the efficacy of felodipine in induced neurons (iN) directly reprogrammed from the FELL-HD patient skin fibroblasts. iNs uniquely keep the genetic and aging signatures of the donor bypassing any stem cell phase. We converted 7 control and 18 HD patients’ fibroblasts to iNs. We used 0.1 and 1 μM felodipine treatment for 24h and 72h. After 28 days of conversion followed by Felodipine treatment iNs were counterstained to determine neuronal morphology and subcellular autophagy changes using high-content automated screening microscopy. Our results showed that at baseline a subset of HD-iNs had reduced neuronal complexity and impaired autophagy. In addition, there is an HD-iN specific effect of Felodipine in enhancing autophagy in some patients while having no effect on others. These preclinical results will be directly compared and correlated with FELL-HD trial patient outcomes. This project has uniquely used an in vitro preclinical iN model in parallel with patients in a trial and it will be of great interest to see how predictive this assay is of clinical effects, which in turn may open up a new approach to clinical trial optimization and personalized medicine figure 1.
Authors: Kinga Vörös, Dimitri Apostolopoulos, Anna Anoir Abbas, Lea Danics, Shaline Fazal, Roger A Barker, Karolina Pircs
Institutions: Semmelweis University, University of Cambridge, Lund University
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4402374308