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TP53 - ACC Therapeutics

The TP53 gene is an essential regulator DNA repair and cell division, and a subset of its variants are highly associated with pediatric AdrenoCortical Carcinomas (ACC).

Pathogenicity: 

Li-Fraumeni syndrome is an inherited form of TP53 variations that cause familial cancer risk. AlphaMissese predicts a significant portion (37%) of 2569 possible changes in TP53 are pathogenic. However only a small subset of Li-Fraumeni variants are associated with inherited adrenocortical carcinoma (ACC) risk. Clinvar lists 57% of 232 clinically-observed ACC-associated missense variants as pathogenic.  As a result, only a fraction (5.1%)  of the possible path in TP53 has been identified as pathogenic for ACC.  Improved diagnostic accuracy and population screening  has the potential to boost the TP53-ACC population by an order of magnitude or more (>10x).

Population: 

There are currently 186 known types of variations in TP53 that contribute to its ACC 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 TP53 can be associated with ACC and tend to exhibit loss of function (PMID: 25584008). Additionally, most of the variants associated with ACC are autosomal dominant.  These results indicate modeling in heterozygous and potentially homozygous states may yield a phenotype that can be screened for drug rescue. In a human iPSC-derived Adrenal Cortex model (AC), the growth defects TP53 can be monitored in a microchip format.

Drugs:  

For discovery and development of drugs to treat pathogenic variants in TP53 - ACC, the deficiencies observed in the AC microchip can be screened against drug libraries (small molecules, ASOs and AAVs) to find hits that restore normal function.  The TP53 gene is considered to be an excellent candidate gene for treating adrenocortical carcinomas because growth aberrations associated loss of function alleles in TP53 may benefit from small molecules that restore stability, or AAV gene replacement techniques.  The most frequent missense alleles in TP53 that are associated adrenocortical carcinomas are the R337H, R158H, and R267W.

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.