Exploring a therapeutic approach to promote neuronal function for ALS

In ALS, several genes have been identified that, when altered, can contribute to disease. A pathogenic variant in the C9orf72 gene is associated with an increased risk of ALS, as well as frontotemporal dementia (FTD). FTD is a form of neurodegenerative disease that can cause changes in behavior and personality. To further explore treatment options for ALS and ALS/FTD, Dr. Liliana Attisano and her team have recently analyzed neurons from a C9orf72 mouse model of ALS. Their research revealed changes in neuron shape and an increased sensitivity to a stress-inducing factor. Focusing on proteins called ALK (Anaplastic Lymphoma Kinase) and LTK (Leukocyte Tyrosine Kinase), which are part of signaling pathways that suppress neuronal repair and growth, the team identified a potential therapeutic approach. Treating the neurons with a drug called lorlatanib, an ALK inhibitor currently approved for cancer treatment, seemed to promote the regrowth of damaged neurons, and protect them from stress factors in the lab.

Building on this discovery, Dr. Attisano plans to investigate whether lorlatanib might support survival and function of neurons from non-C9orf72 ALS. Toward this aim, her team will produce neurons in the laboratory using pluripotent cells (iPSCs) generated from skin samples from people living with the disease. They will then test the effect of the drug on neuronal survival. Additionally, they will use these cells to make cerebral organoids, which are small three-dimensional brain-like structures, complete with other types of cells found near motor neurons. These 3D models are thought to be a better model to study disease processes and the potential efficacy of drugs, as it better replicates the real environment in which cells are found in our body.

Results from this project can provide preclinical evidence for the effectiveness of this drug. If promising, the findings could prompt further studies with the goal of translating their findings into the clinic for people living with ALS and ALS/FTD.

Collaborators: Dr. Janice Robertson

For more than 20 years, ALS Canada funding has played an important role in ALS genetic discoveries, with over 50 research grants awarded that focus on the understanding of ALS genes. We remain committed to supporting the development of gene-based therapies.