Screening platform for peripheral neuropathies in induced pluripotent stem cell derived 2D and 3D models.

Charcot-Marie-Tooth (CMT) neuropathies are progressive peripheral neuropathies resulting in muscle weakness and atrophy. The development of efficient therapies is complicated by the tremendous 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 CMT type 1A. So far, all therapeutic studies have been 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 (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 and a long lead time must be taken in 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. The iPSC technology offers a solution for this. We have recently been able to demonstrate that induced pluripotent stem cell (iPSC)-derived nerve cells from CMT type 2 patients, caused by different gene mutations, share common features. We also showed that we could partially restore progressive mitochondrial dysfunction in these iPSC neurons by means of a therapeutic molecule. The test platform developed by us consists so far of: - Measuring nerve outgrowth; - Determining the axonal transport; - Characterizing the mitochondrial dysfunction; - Phenotyping by means of microscopic techniques. SCREEN4PN aims to further optimize, build and standardize the platform, and most importantly, extend it from a 2D to a 3D cell model by introducing neuromuscular organoids (NMOs). The goal is to offer this 2D and 3D platform to the pharmaceutical industry, clinical research organizations (CROs), and academic institutions. Initially, SCREEN4PN will be a testing platform for CMT-targeted therapies, but this will be extended to other peripheral neuropathies and neuromuscular disorders. The iPSC testing platform (2D and 3D), SCREEN4PN, should significantly shorten the process for testing drug candidates and biomarkers for this diverse group of hereditary neuropathies; by a factor of 5 compared to animal research (from more than a year to 4 months). The cost of screening candidate therapeutic molecules should also be reduced by a factor of 4. The number of experiments and the experimental variability, inherent to animal research, should also reduce. The SCREEN4PN platform, consisting of patient and control-derived iPSC neurons and NMOs (2D and 3D cultures), combined with standardized assays, will benefit the pharmaceutical industry in evaluating and/or validating their therapies or biomarkers in a relevant model; not only for CMT but also for other related neuromuscular and neurodegenerative disorders. The ultimate intention is to offer this niche CRO activity to the pharmaceutical industry, CROs and academia through a Spin In or Spin Off.

Keywords:CHARCOT-MARIE-TOOTH DISEASE

Disciplines:Neurological and neuromuscular diseases