Investigating the Regulatory RNA Landscape of syngap1 for a Novel Target of Therapeutic Upregulation in Patients with Loss of Function Mutations
Abstract number :
3.148
Submission category :
2. Translational Research / 2E. Other
Year :
2022
Submission ID :
2204945
Source :
www.aesnet.org
Presentation date :
12/5/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:27 AM
Authors :
Ali Al Abdullatif, MSc – Camp4 Therapeutics; Gokul Ramaswami, PhD – CAMP4 Tx; Preeti Sathe, MS – CAMP4 Tx; Yeliz Yuva-Aydemir, PhD – CAMP4 Tx; Rutuja Pai, MS – CAMP4 Tx; Scott Waldron, BS – CAMP4 Tx; Stephanie Lefebvre, BS – CAMP4 Tx; Jenna Weinstein, BS – CAMP4 Tx; Evan Cohick, BS – CAMP4 Tx; Bryan Mathews, PhD – CAMP4 Tx; Brynn Akerberg, PhD – CAMP4 Tx; Yuting Liu, PhD – CAMP4 Tx; David Bumcrot, PhD – CAMP4 Tx; Alfica Sehgal, PhD – CAMP4 Tx
Rationale: Noncoding regulatory RNAs (regRNA) have been identified as modulators of gene expression. CAMP4’s RNA Actuating Platform (RAPTM), can generate cell type specific maps of the genome regulatory landscape and identify regRNAs with the goal of discovering a novel therapeutic target capable of upregulating the wild type allele in haploinsufficiency diseases and restoring function._x000D_
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SYNGAP1-related non-syndromic intellectual disability represents approximately 1% of all intellectual disability cases. This disorder is caused by a heterozygous pathogenic mutation in the SynGAP1 gene and presents as moderate to severe intellectual disability with epileptic seizures. Our objective is to identify regRNAs with the ability to modulate SynGAP1 expression and target them using antisense oligonucleotides to upregulate gene abundance to normal levels.
Methods: Next generation sequencing techniques and our proprietary machine learning AI were utilized to map the regulatory RNA landscape of the SynGAP1 gene locus. We identified regRNA transcripts and their abundance across multiple immortalized cell lines and patient iPSC derived neurons and microglia. We modulated these transcripts through various reagents thereby supporting this as a therapeutic strategy for SynGAP1 upregulation.
Results: Our multi-tissue mapping of the regulatory landscape identified non-coding regRNAs linked to the various SynGAP1 isoforms. These regRNAs were present in various cell types including human iPSC derived neurons. Our sequencing data also captured the previously annotated Natural Antisense Transcript (NAT) of SynGAP1. The presence of these transcripts was also confirmed directly from human brain samples through qPCR. An exhaustive experimental approach to targeting SynGAP1 NAT was used to modulate NAT abundance and evaluate actuation of SynGAP1 mRNA. Epigenomic analysis is underway to better understand the mechanism by which SynGAP1 NAT regulates SynGAP1 expression. We have ongoing antisense oligonucleotides screens targeting these regRNAs to assess modulation of the transcription of SynGAP1.
Conclusions: CAMP4 RAP platform can identify regRNAs that control gene expression, thereby providing a tool to modulate gene expression using ASOs. The regRNAs associated with SynGAP1 are correlated with SynGAP1 mRNA. Ongoing screens of oligonucleotides targeting these regRNAs are underway to identify a lead molecule with therapeutic capability of upregulating SynGAP1 in haploinsufficient patient iPSC derived neurons.
Funding: Private Investors: Polaris Partners, Andreessen Horowitz, 5AM Ventures, Northpond Ventures, Alexandria, The Kraft Group
Translational Research