Screening platform for therapies for peripheral neuropathies (SCREEN4PN) in induced pluripotent stem cell derived 2D and 3D models (development phase 2).

SCREEN4PN is a validation platform for therapeutics and biomarkers for Charcot-Marie-Tooth (CMT) neuropathy in induced pluripotent stem cell (iPSC) derived 2D and 3D models. CMT is a progressive peripheral neuropathy resulting in muscle weakness and atrophy in children and adults. The development of efficient therapies is complicated by the clinical and genetic heterogeneity of these incurable hereditary neuropathies. Most CMT therapeutic studies are in a laboratory or pre-clinical phase, and only one phase III clinical study was reached for the most common form, CMT1A. So far, all therapeutic studies are performed in specific small animal models mimicking one specific gene mutation causing a CMT disease subtype. It is only theoretically possible to create an animal model for every gene mutation that causes CMT (which can be caused by more than a thousand mutations), and it involves high cost and ethical objections (3R principle for the use of laboratory animals). In addition, since the disease symptoms typically only appear in (young) adulthood, complications that can arise during the development of transgenic laboratory animals must be taken into consideration. Moreover, the metabolism between humans and small laboratory animals differs significantly, which can have implications for determining the correct dose and the long-term effects of a drug. In January 2022, we started SCREEN4PN thanks to the IOF supporting our first one-year POC proposal. Our test platform developed so far consists of: - Measuring nerve outgrowth - Evaluating axonal transport parameters - Characterizing the mitochondrial dysfunction - Phenotyping by means of microscopy techniques - Measuring expression of key biomarkers (protein or transcript levels) At the start of the project, we recruited an iPSC technologist to optimize our 2D platform. The technologist was immediately involved in providing service to our first industrial client and presented SCREEN4PN at the national and international level. We have also optimized the 3D system, which is the development of neuromuscular organoids, in frame of a valorization trajectory. Based on our experience from working with an industrial partner, for whom we executed a fee for service contract on our state-of-the-art platform (September 2021 – September 2022), we were able to better identify the requirements from industrial partners and detect shortcomings in our current state of the art screening platform. In Q4 we will further test these requirements with other industrial contacts validating their therapeutic compounds in CMT neuropathies. The focus of this new POC application (development phase 2) is to raise the TRL level from 4 to 6 by further fine tuning the 2D platform, by connecting motor neurons to muscle cells through a micro-fluidic device and 3D neuromuscular organoids (NMOs). This will allow for a better readout of the effect of therapeutic compounds administered to these connected cells. Micro-fluidics will further improve SCREEN4PN as it permits standardization and enhances our services provided to pharmaceutical industries and clinical research organizations (CROs) interested in validating their therapeutic molecules or biomarkers. The microfluidic device, as part of the 2D system, will be a relevant addition to the service platform, as the 3D organoid model is more suitable to address a more complex and heterogeneous system. SCREEN4PN (development phase 2) aims to optimize, build and standardize the platform, and most importantly, to expand our platform to include 3D cell models by introducing neuromuscular organoids, alongside our 2D models. SCREEN4PN is designed to become a testing platform for CMT-targeted therapies but will be expanded to include other peripheral neuropathies and neuromuscular disorders. The ultimate intention is to offer this niche CRO activity to the pharmaceutical industry and academia through either a Spin-in or a Spin-off.

Keywords:ORGANOID

Disciplines:Neurological and neuromuscular diseases