Project Overview

Challenge: ALS (amyotrophic lateral sclerosis) is an incurable and invariably fatal motor neuron (MN) disease. Our challenge is to develop a biologic-therapy that slows, halts or functionally reverses ALS progression.

Solution: ALS is characterized by the toxic mislocalization of a hyperphosphorylated form of TAR DNA binding protein-43 (TDP-43) within MNs. Progranulin counters this toxicity, and, crucially, it both increases neuronal survival and attenuates harmful neuroinflammatory reactions. Progranulin mediates much of its activity through the regulation of lysosomal activity and autophagy. It is processed into smaller biologically active polypeptides called granulins within lysosomes, however lysosomal function is highly disordered in neurodegenerative diseases, including ALS. We hypothesize that this blunts the therapeutic action of progranulin. We propose, therefore, to develop biological agents based on the granulins and granulin combinations to circumvent the lysosomal processing stage of mature progranulin. The optimal formulation of granulins will be selected by in vitro evaluation of MN survival, preservation of morphology, and protection from TDP-43 toxicity, in conjunction with their ability to promote protective versus adverse microglial phenotypes. The two best performing granulin formulations will be inserted into Adeno-associated viral (AAV) vectors and delivered to the CNS of TDP-43-ALS mice via intra-cisterna magna injection. The preservation of motor function, reduction of motor neuron attrition and neuroinflammation will be quantified and benchmarked against corresponding full-length progranulin AAV.

Expected Achievements/Impact: Successful development of a well-validated granulin based formulation suitable for IND submission. A granulin-based therapy will markedly improve the lives of ALS patients offering the potential of improved quality of life, survival, and possibly functional recovery. It will provide a significant boost to the Neurodyn Inc’s. progranulin program and allow an important scale up of operations within Quebec.

Principal Investigator

Andrew Bateman , Research Institute McGill University Health Centre

Team Members

Andrew Tasker, University of Prince Edward Island

Jay Penney, University of Prince Edward Island

Partners and Donors

CQDM

Neurodyn Life Sciences Inc.