GABABR1a sushi domain activators

 



PMP22 is a component of myelin, the protective layer that covers nerve cells and promotes the efficient transmission of impulses. Genetic duplication of PMP22 causes the most common form of CMT, CMT1A. Activation of GABABR, the metabotropic receptor for the inhibitory neurotransmitter GABA, has been shown to reduce the expression of PMP22 and therefore offers a promising therapeutic strategy for CMT1A. The extra gene leads to overproduction of the protein and destabilizes myelin. Indeed, treatment with the GABA analog baclofen has been shown to improve myelination, axonal parameters, and motor functions in a CMT1A mouse model. Activators that are currently in clinical development lack specificity, leading to adverse effects. Their dose-limiting effects and poor safety margins make them unsuitable for chronic use in the treatment of progressive neurological disorders.

Using a platform that combines biophysical and biochemical assays, structural biology, and isoform-specific models, we are developing novel subtype-selective GABABR1a activators with a broader therapeutic window and an improved safety profile. Our approach is based on the discovery that a short (17 AA) peptide, derived from the secreted amyloid-β precursor protein (sAPPα), binds selectively to the Sushi 1 domain, which is present only in GABABR1a.  We successfully demonstrated that spontaneous neuronal activity is suppressed ex vivo by our novel sAPPα-based ligands.

Activators that are currently in clinical development lack specificity, leading to adverse effects. Their dose-limiting effects and poor safety margins make them unsuitable for chronic use in the treatment of progressive neurological disorders. Using a platform that combines biophysical and biochemical assays, structural biology, and isoform-specific models, we are developing novel subtype-selective GABABR1a activators with a broader therapeutic window and an improved safety profile. Our approach is based on the discovery that a short (17 AA) peptide, derived from the secreted amyloid-β precursor protein (sAPPα), binds selectively to the Sushi 1 domain, which is present only in GABABR1a.  We successfully demonstrated that spontaneous neuronal activity is suppressed ex vivo by our novel sAPPα-based ligands.


Joris de Wit, PhD: Scientific Founder

"The identification of novel subtype-selective GABABR1a ligands that bind specifically to the sushi 1 domain and modulate neurotransmission in vivo is a major step toward the development of a safe and effective isoform-specific GABABR-based therapeutic for CMT"

Rice HC, de Malmazet D, Schreurs A, Frere S, Van Molle I, Volkov AN, Creemers E, Vertkin I, Nys J, Ranaivoson FM, Comoletti D, Savas JN, Remaut H, Balschun D, Wierda KD, Slutsky I, Farrow K, De Strooper B, de Wit J. Secreted amyloid-β precursor protein functions as a GABABR1a ligand to modulate synaptic transmission. Science. 2019 11;363(6423):eaao4827



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