Development of antisense oligonucleotides for SYNGAP1 haploinsufficiency associated with autism spectrum disorder and intellectual disability
- Awarded: 2020
- Award Type: Pilot
- Award #: 731581
Precise synaptic connectivity and plasticity are critical for human cognition. Changes in synapse development, maturation and plasticity can lead to a variety of conditions, including intellectual disability (ID), autism spectrum disorder (ASD) and schizophrenia. Recent genetic studies have revealed that genes regulating the function of glutamatergic synapses are strongly associated with these disorders.
SYNGAP1, which encodes a neuronal Ras GTPase activating protein, is one of the most significant risk genes for ID and ASD. Deleterious de novo SYNGAP1 mutations are estimated to account for approximately one percent of nonsyndromic ID, and recent exome sequencing studies implicate SYNGAP1 as one of the top ASD-associated risk genes. Studies in vitro and in heterozygous knockout mice have shown that SYNGAP1 is critical for brain development, synaptic plasticity, and learning and memory.
SYNGAP1-related intellectual disability (SRID, also known as MRD5) is a highly penetrant monogenic neurodevelopmental disorder characterized by ID, ASD and epilepsy. As many of the genetic mutations in individuals with SRID lead to haploinsufficiency of SYNGAP1, SRID is an ideal candidate for genetic and antisense oligonucleotide–based therapies that increase expression from the remaining functional allele.
Informed by recent findings of a poison exon extension in SYNGAP11, distinct functions of Syngap1 splice isoforms in mouse neurons2, and the identification of a natural antisense transcript in the mouse brain (Syngap1-AS)3,4, Richard Huganir and his colleagues propose designing precision antisense oligonucleotides (ASOs) to increase SYNGAP1 expression. To validate ASO candidates and establish dosage-response measurements relevant to individuals with SRID, human-induced pluripotent stem cell lines with loss-of-function heterozygous mutations in SYNGAP1 introduced through CRISPR/Cas9 genome editing will be used to assess the ability of candidate ASOs to enhance expression levels of SYNGAP1 from the remaining functional allele.
Through this approach, Huganir’s team plans to leverage recently uncovered properties of SYNGAP1 splicing and expression to develop novel therapeutic strategies and breakthrough candidates for the treatment of SRID. Findings from these studies will also help to advance our understanding of the therapeutic potential of ASO-based treatments for other monogenic forms of ID and ASD.