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AARS1 - CMT Therapeutics

The AARS1 gene is a aminoacyl-tRNA synthetase and its pathogenic variants can cause Charcot-Marie-Tooth (CMT) disease, as well as Developmental and Epileptic Encephalopathy, and others genetic conditions.

Pathogenicity: 

AlphaMissese predicts a significant portion (44%) of 6371 possible changes are pathogenic in AARS1. However Varsome.com only list 3.5% of the711 clinically observed missense variants as pathogenic.  As a result, only 0.9% of the possible path has been verified as pathogenic.  Improved diagnostic accuracy has the potential to boost the populations by more than an order of magnitude (>10x).

Population: 

There are currently 78 known types of variations in AARS1 that contribute to its disease presentation.  We know that well organized patient advocacy groups often will have populations an order of magnitude larger (near 800 patients) for a gene of similar frequency in pathogenicity presentation.

Biomarkers: 

Variants in AARS1 can be associated with either loss of function and gain of function. Additionally some variants are autosomal dominant while some are autosomal recessive.  These results indicate modeling in both heterozygous and homozygous states may yield phenotypes that can be screened for drug rescue. In a human iPSC-derived NeuroMuscular Junction model (NMJ), the neuronal defects AARS1 can be monitored in a microchip format.

Drugs:  

For discovery and development of drugs to treat pathogenic variants in AARS1, the deficiencies observed in the NMJ microchip can be screened against drug libraries (small molecules, ASOs and AAVs) to find hits that restore normal function.  One promising target for regulation are modulators of neuropilin 1 (Nrp1) as as a potential generalized mechanism for tRNA synthetase pathologies associated with Charcot-Marie-Tooth (CMT) disease (PMID: 33753480). However a much larger portion of protein truncating variants throughout the gene have been found to be associated with CMT, which indicates that loss of protein function is a major driver of disease. Thus therapies that restore function by either stabilizing loss of function alleles (small molecules)  or increasing expression of normal AARS1 (ASO and AAV)  are likely to be effective.

Special Purpose Exit Company (SPEC)

Devinebio creates entities (SPECs) to develop drug assets for a specific indications. Five areas are monitored per each SPEC: population, biomarkers, leads, IP, and regulatory. A SPEC’s assets are moved through the milestones of preIND, IND, preNDA and NDA. As a drug asset progresses, it becomes de-risked and it increases in value. Once a drug asset has achieved IND-enabled status, it will have matured enough to be ready for partnering with Pharma.