A New Genetic Medicine Strategy For Treating Neurological Disorders

SUMMARY

• Synaptic transmission and plasticity are fundamental to neuronal functions, and alterations of synaptic protein expression are direct causes of autism, intellectual disability (ID), and epilepsy.

• De novo loss-of-function (LoF) mutations in SYNGAP1, encoding the synaptic Ras GTPase-activating protein, are among the most prevalent causes of ID and autism spectrum disorders.

• Alternative splicing coupled with nonsense-mediated mRNA decay (AS-NMD) is a translation-dependent mechanism which promotes the degradation of mRNAs with premature translation-termination codons.  Recent success in splice-switching oligonucleotides (SSOs) suggests that redirection of splicing through SSO ablations is a viable approach to rescue haploinsufficiency.

• The faculty inventor has designed SSOs to suppress critical intronic elements essential for premature translation termination allowing for increased productive transcripts of SYNGAP1 in neurons.

FIGURE

ADVANTAGES

ADVANTAGES

• Higher efficiency in repressing SYNGAP1 AS-NMD  leading to increased Syngap1 protein detection

• Lower toxicity to neurons

APPLICATIONS

• Autism Spectrum Disorder

• Intellectual Disorder

• Epilepsy

• Validated through human induced pluripotent stem cell-derived neurons

PUBLICATIONS

• Yang, R., et al. (2023). Upregulation of SYNGAP1 expression in mice and human neurons by redirecting alternative splicing. Neuron. Mar 3.