Development of CM-CS1 CAR Treg to Treat Amyotrophic Lateral Sclerosis (ALS)

SUMMARY Amyotrophic lateral sclerosis (ALS) patients develop fatal paralysis as a result of progressive motor neuron loss in the brain and spinal cord. There are more than 5,000 new cases of ALS per year in the United States, with typical age of onset between 40 and 70 years of age. While SOD1 is a cytoplasmic protein, misfolded SOD1 can be secreted and form extracellular oligomers and aggregates. Mutations in superoxide dismutase-1 (mSOD1) result in misfolding and aggregation of SOD1 and are found in a subset of familial ALS cases. However, misfolded SOD1 has also been identified in spinal cord samples from many sporadic cases of ALS. Regulatory T cells (Tregs) have tolerogenic and anti-inflammatory functions and are being pursued as cell-based therapeutics to block auto-inflammatory immune cells. Higher numbers of Tregs (CD4+CD25hiCD127lo) in ALS patients are associated with a slower disease progression. We have developed novel chimeric antigen receptors (CARs) that recognize aggregated SOD1 and trigger Treg function. In this manner, we aim to provide a large number of Tregs that are specific for a disease-associated protein and will become activated at the site of misfolded, aggregated SOD1. We have further enhanced the activity of CAR Tregs by engineering them to produce BNDF, a key neuronal survival factor. We have developed a novel mouse model for ALS by breeding the G93A SOD1 transgene onto the NSG mouse background to create mSOD1-NSG mice. These mice allow the engraftment of human cells and they develop a progressive disease resulting in inflammation in the spinal cord and limb paralysis that mimic findings in ALS. The aim of this project is to perform IND-enabling studies required for translation of this therapy into the clinic.