D - Oligonucleotide Therapeutics (including siRNAs, aptamers, antagomirs, miRNAs, shRNA, antisense, and splice switching oligos, plasmids)
336: Modulation of Somatic Repeat Expansion with Small Interfering RNAs
Type: Oral Abstract Session
Presentation Details
Session Title: Oligonucleotide Therapeutics
Huntington’s disease (HD) is a neurodegenerative disorder affecting 7/100,000 people with no treatment available. HD is caused by CAG trinucleotide repeats in exon 1 of the huntingtin gene. Symptoms including chorea, hemiballism, and depression present at >37 CAG repeats, with the age of disease onset decreasing as CAG repeat length increases. The somatic CAG expansion in striatal medium spiny neurons primarily contributes to age-driven HD neurodegeneration. Human GWAS have associated multiple mismatch repair (MMR) pathway components in HD progression. MMR mediates the expansion of trinucleotide repeats by facilitating strand cleavage of slipped loop intermediates during transcription. Blockage of somatic expansion slows HD progression in mice. Thus, MMR-driven somatic expansion is a therapeutically targetable driver of HD. Potent and selective CNS RNAi is now possible with di-valent siRNA. Here, we have screened, identified, and validated potent siRNA silencing key MMR proteins. Using these di-valent siRNA, we performed a systematic evaluation of the impact of RNAi-based silencing of single MMR components on somatic repeat expansion in vivo in the Q111 mouse model of HD. We have so far identified that RNAi-based interventional lowering of MSH3, PMS1, and MLH1 each blocks somatic expansion. This work allows a mechanistic understanding of the key players facilitating somatic expansion in HD and represents a therapeutic category of repeat-expansion blocking agents. These siRNAs can be used alone or in combination to manipulate somatic expansion as a potential HD intervention. Further, the work presented here informs novel, RNAi-based treatment options for HD and similar trinucleotide repeat disorders.
Jillian Belgrad1, Daniel O'Reilly1, Ellen Sapp2, Ashley Summers1, Eric Luu1, Nozomi Yamada1, Hassan Fakih1, Raymond Furgal1, Nicholas Gaston1, Sarah Allen1, Allison Maebius1, Katherine Gross1, Dimas Echeverria1, Neil Aronin1, Marian DiFiglia2, Anastasia Khvorova1
1UMass Chan Medical School, Worcester, MA,2Massachusetts General Hospital, Mass General Institute for Neurodegenerative Disease (MIND), Charleston, MA"
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