[R21] Defining the potential of GSK3 inhibition in correcting the molecular phenotypes of CTNNB1 syndrome patient derived glutamatergic neurons.
Ente: National Institute of Neurological Disorders and Stroke
Scadenza: 2028-08-31
Importo max: $453,750
Paese: US
Descrizione
PROJECT SUMMARY/ABSTRACT
CTNNB1 syndrome is a severe neurodevelopmental disorder, with developmental delays apparent within the
first postnatal months and lifelong impact on learning, language, and walking capabilities. There are currently
no treatment options beyond supportive care and CTNNB1 syndrome patients often require lifelong care and
assistance for daily functioning. Recent studies identify CTNNB1 pathogenic variants as a lead genetic cause
in a subset of patients misdiagnosed with cerebral palsy. In addition to CTNNB1, several other human gene
mutations that link to intellectual disabilities and autism also cause reduced β-catenin levels and/or functions.
These disorders further highlight the importance of gaining new insights into corrective treatments for
CTNNB1/β-catenin dysregulation and may benefit from the therapeutic strategies that we are developing for
CTNNB1 syndrome. Our preclinical in vivo mouse and in vitro human cell model studies provide the first
evidence for an efficacious therapeutic by showing that a small molecule GSK3α,β inhibitor, exhibiting the
highest selectivity, potency and brain exposure, significantly normalizes β-catenin levels and phenotypes
relevant to human CTNNB1 syndrome. This inhibitor overcomes limitations seen with earlier GSK3 inhibitors in
clinical and preclinical studies of other disorders due to sub-optimal potency or brain exposure and poor overall
kinome selectivity when systematically evaluated in large-scale screening. Our proposed patient derived co-
culture studies will provide critical evidence for the therapeutic efficacy of the lead compound and advance the
design of clinical trials likely to provide beneficial therapeutic outcomes in individuals with CTNNB1 syndrome.
Developing a treatment that improves the learning and motor disabilities would be transformative for CTNNB1
syndrome patients and their families.
Istituzione: TUFTS UNIVERSITY BOSTON
PI: Jonathan Alexander
Progetto: 1R21NS144529-01A1
Settori: National Institute of Neurological Disorders and Stroke
Vai al bando originale
Registrati gratis su Bandolo per trovare bandi compatibili con la tua azienda.