Developing a transformative therapy for inherited homocystinuria by correcting the misfolding of cystathionine beta synthase disease alleles (360G-Wellcome-099376_Z_12_Z)

This Pathfinder Award brings together world-class researchers from Pfizer Inc.’s Rare Disease Research Unit in Cambridge, MA (US), including Dr Christine Bulawa of Pfizer, and the Structural Genomics Consortium (SGC) in Oxford (UK), including Dr Wyatt Yue, to study cystathionine beta synthase (CBS) deficiency. CBS deficiency is a rare genetic disorder in which affected people cannot process the amino acid methionine. In many patients, a genetic defect causes the CBS enzyme to lose its optimal three-dimensional shape and prevents the enzyme from functioning properly. This leads to the build up of homocysteine in the body, causing an array of symptoms including early cardiovascular disease. The current standard of care is to reduce homocysteine levels by a methionine-restricted diet or supplementation with vitamin B6, a cofactor for the CBS enzyme. However, this does not treat the underlying cause of the disease, and many patients do not respond to these treatments. During the course of this collaborative research, scientists at Pfizer and SGC aim to develop biochemical and molecular tools to facilitate discovery of a potential drug that restores the optimal shape and function to the defective CBS protein, thereby treating the root cause of the disease.