Commercial production of alpha-synuclein fibrils amplified from human postmortem brain tissue to expand the availability of a critical research tool for Parkinson's disease

Helical Biosciences Llc, Saint Louis MO

Investigators

Abstract

Helical Biosciences is a startup company formed to commercialize technology developed at Washington University School of Medicine. The goal of this project is to develop Lewy fold fibrils (LFFs), a new research tool that overcomes a significant barrier to developing effective treatments for Parkinson’s disease (PD) and Lewy body dementia (LBD). PD is a neurodegenerative disease that affects over 1 million people in the US and causes progressive impairment of movement and cognitive function. The majority of people with PD develop dementia, known as Lewy body dementia (LBD). The defining feature of PD is the accumulation of alpha-synuclein (Asyn) fibrils in neurons throughout the brain. These Asyn fibrils have highly ordered beta sheet protein structure and accumulate in neuronal cells to form cytoplasmic and neuritic inclusions known as Lewy bodies and Lewy neurites. Asyn fibrils are currently a major focus for research and development (R&D) efforts that aim to understand disease mechanisms, to develop diagnostics that quantify Asyn fibril accumulation in living individuals, and to develop therapeutics that prevent, slow or remove Asyn fibril accumulation. Current R&D efforts rely heavily on in vitro preparations of Asyn fibrils, prepared using methods that induce soluble Asyn protein to form fibrils in vitro. Recent studies indicate that the structure of in vitro fibril preparations is substantially different from the structure of ex vivo PD fibrils obtained from human postmortem brain tissue. However, the quantities of fibrils extracted from postmortem tissue samples are orders of magnitude lower than what are needed for R&D efforts. Lewy fold fibrils (LFFs) are an amplified preparation of ex vivo fibrils that replicate the structure of ex vivo PD fibrils and that can be produced on a scale sufficient to meet R&D needs. In this project we will determine the feasibility of commercial production of LFFs. We will produce batches of LFFs at increasing scale and then determine whether batches of commercially produced LFFs have the key structural features that distinguish LFFs from in vitro Asyn fibrils, based on analysis of cryo - EM data, fluorescent ligand binding assays, and fibril growth assays. The protocol for commercial production will be optimized to meet these structure-based criteria. The results of this project will provide key feasibility data for commercialization of LFFs and for the development of additional applications such as animal models based on LFFs.