Abstract Details

Title Diplotype-based Expanded Use of Individualized Allele-specific Antisense Oligonucleotides

Topic General Neurology

Presentation(s) P5 - Poster Session 5 (11:45 AM-12:45 PM)

Poster/Presentation
Number 7-013

Objective To report a pathway for broader use of individualized allele-specific antisense oligonucleotides through diplotyping

Background Antisense oligonucleotides (ASOs) are short oligodeoxynucleotides designed to address underlying causes of genetic diseases by altering RNA processing and protein expression. They are engineered to target a patient's particular genetic variant, enabling the development of individualized treatments for rare genetic diseases. Allele-specific ASOs that selectively downregulate the allele containing the deleterious variant responsible for disease via a gain-of-function mechanism have demonstrated clinical efficacy. A notable example comes from an n-of-1 clinical trial utilizing an individualized, allele-specific ASO that resulted in substantial seizure reduction and improvement in neurodevelopmental in a patient with SCN2A-related disorder (SRD). This ASO targets the mRNA for degradation by binding to the site of a common single nucleotide polymorphism (SNP) located on the same allele as the disease-causing variant. Identifying patients with the appropriate diplotype amenable to this ASO treatment necessitates accurate haplotype phasing of target SNP and disease-causing variant. However, determining phasing accurately is challenging with standard paired-end short-read sequencing.

Design/Methods Novel whole genome sequencing (WGS) technology facilitates ultra-long phasing by utilizing cluster proximity information to overcome this limitation. Using this technology to confirm phasing of de novo disease-causing variant and target SNP, we analyzed a cohort of SRD patients to assess potential reach of the ASO therapy.

Results

19 probands were diagnosed through rapid WGS between 2018-2024. Ages at diagnosis ranged from 2-weeks to 12-years-old. The target SNP was harbored by eight (42%) patients. Three (16%) were confirmed to have the correct SNP configuration amenable to ASO.

Conclusions We demonstrate an innovative approach to broaden use of individualized ASOs. Targeting common SNPs rather than solely disease-causing variants, this offers potential benefits for a wider range of SRD patients and promise for application in other genetic disease.

Authors/Disclosures
Olivia S. Kim Mcmanus, MD (University of California San Diego Neurosciences/Rady Children's Institute for Genomic Medicine) PRESENTER	Dr. Kim Mcmanus has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biomarin. Dr. Kim Mcmanus has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biomarin. Dr. Kim Mcmanus has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Praxis Precision Medicines. Dr. Kim Mcmanus has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Stoke Therapeutics. Dr. Kim Mcmanus has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Illumina. Dr. Kim Mcmanus has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB . Dr. Kim Mcmanus has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Illumina . Dr. Kim Mcmanus has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for UCB. Dr. Kim Mcmanus has received research support from California Institute for Regenerative Medicine. The institution of Dr. Kim Mcmanus has received research support from National Institutes of Health/NCATS.
Shahad Olsson, CGC	Mrs. Olsson has nothing to disclose.
Liana Protopsaltis, MS, CGC	Mrs. Protopsaltis has nothing to disclose.
Joseph G. Gleeson, MD	Prof. Gleeson has received personal compensation for serving as an employee of Ionis. Prof. Gleeson has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Neurocrine.
wenfei zhang, PhD	No disclosure on file
Nafeesa Kahn (Illumina, Inc.)	No disclosure on file
Ali Crawford, PhD	Dr. Crawford has received personal compensation for serving as an employee of Illumina. Dr. Crawford has or had stock in Illumina.
Stephen Kingsmore (Rady Children's Institute for Genomic Medicine)	Stephen Kingsmore has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Third Rock Ventures. Stephen Kingsmore has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AB2 Bio. Stephen Kingsmore has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Illumina. Stephen Kingsmore has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ACMGG. Stephen Kingsmore has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Takeda. Stephen Kingsmore has received personal compensation in the range of $500,000-$999,999 for serving as an officer or member of the Board of Directors for Rady Children's Institute for Genomic Medicine. Stephen Kingsmore has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Sidra Medicine. Stephen Kingsmore has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer Nature. The institution of Stephen Kingsmore has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Cold Spring Harbor Press. Stephen Kingsmore has stock in Third Rock Ventures. The institution of Stephen Kingsmore has received research support from Alexion, Amgen, Biomarin, Chiesi, Inozyme, Ionis, Mahzi, Orchard, Sanofi, Rocket, Sarepta, Sentynyl, Travere, Ultragenyx. The institution of Stephen Kingsmore has received research support from NIH. Stephen Kingsmore has received intellectual property interests from a discovery or technology relating to health care. Stephen Kingsmore has received intellectual property interests from a discovery or technology relating to health care.

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