DEVELOPING CELL-BASED BIOASSAYS FOR CLINICAL TRIALS – THE USE OF PATIENT-DERIVED INDUCED NEURONS TO STUDY AUTOPHAGY IN THE FELL-HD CLINICAL TRIAL

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansions in the huntingtin (HTT) gene, leading to the production of mutant huntingtin protein (mHTT). The disease typically presents in midlife and is currently incurable. Impaired autophagy, a lysosomal degradation pathway essential for cellular homeostasis, contributes to mHTT accumulation and disease pathogenesis.
Preclinical studies have shown that felodipine enhances autophagy and promotes clearance of protein aggregates in animal models of HD. Based on these findings, the FELL-HD phase II clinical trial was conducted to assess the tolerability and feasibility of felodipine treatment in patients with early-stage HD. As autophagy cannot be directly examined in the living human brain, we investigated drug effects using induced neurons (iNs) directly reprogrammed from skin fibroblasts obtained from FELL-HD participants. These transdifferentiated neurons retain the genetic, epigenetic, and aging signatures of the donor.
Fibroblasts from 7 control individuals and 18 HD patients were converted into iNs with high efficiency and purity. DNA methylation analysis revealed accelerated epigenetic aging in a subset of HD-derived iNs.Morphological assessment demonstrated reduced neuronal complexity and increased HTT expression in most HD-iNs. Following 28 days of neuronal conversion, cells were treated with felodipine for 24 hours.
Felodipine enhanced autophagy in only a subset of patient-derived iNs, without detectable adverse effects. Importantly, preclinical autophagy readouts correlated with patient-specific responses observed in the FELL-HD trial. This study highlights the utility of patient-derived iNs as a translational platform to investigate drug mechanisms inaccessible in the living human brain.