Special Purpose Exit Company (SPEC)

learn more

CTNNB1-NDD Therapeutics

The CTNNB1 gene is a beta-catenin whose pathogenic variants can cause the Neurological Development Disorder (NDD) of severe intellectual disability-progressive spastic diplegia syndrome, and CTNNB1 is also involved in various cancers.

Pathogenicity: 

AlphaMissese predicts a significant portion (63%) of 5180 possible changes are pathogenic in CTNNB1. Varsome.com lists 18% of the 306 clinically observed missense variants as pathogenic.  As a result, only 1.7% 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 275 known types of variations in CTNNB1 that contribute to its disease presentation.  We know that well organized patient advocacy groups often will have populations an order of magnitude larger (near 2000 patients) for a gene of similar frequency in pathogenicity presentation.

Biomarkers: 

Variants in CTNNB1 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 CTNNB1 can be monitored in a microchip format.

Drug Candidates:  

For discovery and development of drugs to treat pathogenic variants in CTNNB1, 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.  The CTNNB1 gene is considered to be an excellent candidate gene for treating neurodevelopment disorders by promoting the formation of the adhesion complex, which is present in both pre- and post- synaptic regions and has a significant impact on the modulation of synapse formation and synaptic plasticity (PMID: 37009120).  With a dominant portion of the variations in CTNNB1 being observed as Protein Truncating Variants (PTVs), loss of function is a conspicuous mechanism to the neurodevelopmental disorder observed with CTNNB1 variations.  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.  The most frequent alleles in CTNNB1 that are associated neurodevelopmental disorder are the G575R missense variant and PTVs of Y326*, R515* and R661*. iPSC platforms made with these alleles can be used to screen a wide variety of drug modalities.

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.