Somatic Expansion Targets

Part of MutSbeta complex (MSH2-MSH3). Recognizes CAG repeat loops that form during DNA repair. When 3+ MutSbeta molecules bind, they resist dissociation and recruit endonuclease activity. MSH3 is rate-limiting: 50% reduction in MSH3 leads to ~50% less expansion.

High. siRNA/shRNA knockdown demonstrated in animal models. Multiple companies developing MSH3-targeted drugs.

• siRNA/shRNA targeting MSH3 (90/100 confidence)
• LQT-23 (LoQus23, allosteric inhibitor, IND 2026)
• Di-valent siRNA (single dose blocks expansion 4 months)

A protective DNA repair nuclease that opposes somatic expansion. Has the strongest genetic association to delayed disease onset. Works via PCNA-mediated assembly to target the expanded strand, directing nuclease activity to remove loops (contraction). Also has a nuclease-independent protective mechanism.

Medium. Upregulation (not inhibition) is the goal. Harness Therapeutics developing HRN001 (MISBA platform) for FAN1 upregulation.

• HRN001 (Harness Therapeutics, ASO, FIH 2027)
• miR-124-3p antagomir (FAN1 upregulation via mRNA site blocking)

Part of the MutL family. Homozygous PMS1 inactivation reduces CAG repeat expansion. A pseudoexon in PMS1 can be targeted by splice modulators to reduce PMS1 protein levels dose-dependently, suppressing somatic expansion while preserving enough normal MMR to avoid cancer risk.

High. Splice modulation demonstrated. SKY-0515 (Skyhawk) already in Phase 2/3 clinical trial (FALCON-HD).

• SKY-0515 (Skyhawk, Phase 2/3, 62% mHTT + 26% PMS1 reduction)
• RGT-0474060 (Rgenta, oral PMS1 inhibitor, preclinical)
• Branaplam (Novartis, discontinued due to neuropathy, but validated mechanism)

Forms MutLgamma complex with MLH3 (MLH1-MLH3). MutLgamma is an endonuclease that nicks DNA opposite the CAG loop, generating nicks that enable displacement synthesis. Reduced MLH1 slows repeat expansion the most of all MutL family members. A point mutation in MLH3's endonuclease domain completely eliminates CAG expansion.

Medium. Gene knockdown demonstrated in cell models. Challenge: MLH1 is also critical for cancer prevention (Lynch syndrome).

• Cyclic peptide inhibitors of MLH1-MSH3 interaction (nanomolar potency, academic)
• MLH3 splice redirectors (exon skipping, preclinical)

Seals nicks during DNA repair, locking in the expanded CAG repeats. The K845N variant is associated with a 7-8 year delay in motor onset, one of the strongest single-modifier effects known. K845N enhances discrimination against mismatched substrates (increases repair fidelity). Published in PNAS, March 2026.

Emerging. Small molecules that increase ligase fidelity could mimic the K845N protective effect. No clinical candidates yet.

• Ligase fidelity enhancers (concept stage, based on K845N mechanism)
• No named clinical candidates yet