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allele-selective-oligonucleotides

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aliasesallele-selective ASO, SNV-selective siRNA, allele-specific oligonucleotide therapy, mutant-allele-selective RNA therapy, oligonucleotide therapeutics

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Allele-selective oligonucleotides

A clinically mature pharmacological class targeting RNA sequences via Watson-Crick base pairing. Multiple FDA-approved drugs demonstrate that RNA-targeting oligonucleotides can achieve durable knockdown of specific transcripts with acceptable safety profiles. The class’s aging-biology relevance is prospective: the same sequence-selectivity logic that enables disease-gene targeting could in principle be applied to clonally expanded somatic mutations — CHIP driver mutations (DNMT3A, TET2, JAK2), the GNAQ Q209L mosaic SNV driving cherry angiomas, and other age-associated mutant alleles — where selective degradation of the mutant transcript could clear or suppress clonally expanded cells while sparing wild-type counterparts.

This page covers the pharmacological class as a whole. Specific drugs would live as compound pages in molecules/compounds/ if seeded. See intervention-by-target-immunogenicity for the framework distinguishing direct molecular approaches (Tier 2) from immune-surveillance approaches (Tier 1) for somatic mosaic targets.

1. What this class is

Oligonucleotide therapeutics are synthetic polymers of 15–30 nucleotides, chemically modified to resist nuclease degradation. Two principal effector mechanisms determine RNA fate:

Antisense oligonucleotides (ASOs)

Single-stranded DNA/RNA hybrids, typically 18–25 nt, with phosphorothioate (PS) backbone and 2’-O-methoxyethyl (2’-MOE), locked nucleic acid (LNA), or phosphorodiamidate morpholino (PMO) sugar modifications. Two ASO mechanisms:

  • RNase H recruitment (gapmer ASOs): The central DNA “gap” of a gapmer (typically 8–12 nt flanked by 2’-modified RNA “wings”) hybridises to a complementary mRNA, recruiting RNase H1 to cleave the RNA strand of the resulting RNA:DNA heteroduplex. The ASO is recycled and can catalytically degrade multiple transcripts. This is the mechanism of most FDA-approved ASOs (inotersen, tofersen, mipomersen).

  • Steric splice modulation (PMO/LNA ASOs): Fully modified single-stranded ASOs that sterically block splice enhancer or silencer sequences without recruiting RNase H, redirecting spliceosomal exon inclusion/skipping. Mechanism of nusinersen (SMN2 exon 7 inclusion) and the DMD exon-skipping drugs.

Small interfering RNA (siRNA)

Double-stranded 19–21 nt RNA duplexes with 2-nt 3’ overhangs. The guide (antisense) strand is loaded into the RISC/AGO2 complex, which then performs endonucleolytic cleavage of complementary mRNAs. siRNA drugs require delivery vehicles (lipid nanoparticles, LNP; or GalNAc conjugates for hepatic targeting). FDA-approved siRNA drugs: patisiran, vutrisiran, givosiran, lumasiran, inclisiran.

Allele-selectivity — the key mechanistic differentiator

Most approved oligonucleotide drugs target the wild-type RNA of a disease-causing gene (e.g., patisiran silences mutant TTR gene transcripts, which are uniformly expressed in all hepatocytes). Allele-selective programs, by contrast, exploit the thermodynamic difference in hybridisation energy when an oligonucleotide overlaps a SNV position:

  • A perfect match contributes approximately +1.5–2 kcal/mol stability vs. a single central-position mismatch.
  • This differential is sufficient for RNase H or RISC to discriminate mutant from wild-type RNA — but the window is narrow and position-dependent: a mismatch at position 10 (opposite the AGO2 cleavage site for siRNA, or the RNase H cleavage window for ASOs) produces the most discrimination; terminal-position mismatches are poorly discriminating.
  • Chemical modifications (LNA insertions, boranophosphate) can widen the discrimination window at the mismatch position.

Why this matters for aging: Age-related clonal expansion is driven by somatic SNVs, not by uniform gene overexpression. Targeting the wild-type transcript would harm all cells. Allele-selective oligonucleotides would selectively reduce or silence only the mutant-allele-bearing clones — conceptually equivalent to a gene therapy without permanent genome modification.

2. Clinical landscape — FDA-approved drugs

Important framing: The drugs below are approved for inherited monogenic diseases. They demonstrate the class’s clinical maturity (safety, delivery, regulatory pathway) but are NOT allele-selective in the strict sense. They establish proof-of-concept that oligonucleotides can be systemically delivered and achieve durable, well-tolerated target knockdown in humans.

RNAi (siRNA) drugs

DrugTargetIndicationFDA approvalPivotal trialRouteAllele-selective?
Patisiran (Onpattro)TTR mRNA (hepatic)hATTR amyloidosis with polyneuropathy2018 (first siRNA drug)APOLLO 1IV infusion (LNP)No — silences all TTR
Vutrisiran (Amvuttra)TTR mRNA (hepatic)hATTR amyloidosis with polyneuropathy2022HELIOS-A 2SC injection (GalNAc)No
Givosiran (Givlaari)ALAS1 mRNAAcute hepatic porphyria (AHP)2019ENVISION 3SC injection (GalNAc)No
Lumasiran (Oxlumo)HAO1 mRNAPrimary hyperoxaluria type 1 (PH1)2020ILLUMINATE-A 4SC injection (GalNAc)No
Inclisiran (Leqvio)PCSK9 mRNAHeterozygous FH / high CV risk2021ORION-9 5SC injection (GalNAc)No (though it silences PCSK9, which has LOF variants used in GWAS — not SNV-targeted per se)

Patisiran (APOLLO trial) 1: First FDA-approved siRNA drug. APOLLO (n=148 patisiran, n=77 placebo) demonstrated a least-squares mean change in mNIS+7 of −6.0 ± 1.7 in the patisiran group versus +28.0 ± 2.6 in the placebo group at 18 months (difference −34.0 points; P<0.001). Primary endpoint met. LNP formulation required pre-medication (dexamethasone + antihistamines) to prevent infusion reactions.

Vutrisiran (HELIOS-A trial) 2: GalNAc-conjugated siRNA, quarterly SC injection. Primary endpoint — change from baseline in mNIS+7 at 9 months — met (P=3.54×10⁻¹²). No pre-medication required. Longer dosing interval (once quarterly) vs. patisiran (once every 3 weeks IV) represents a substantial convenience improvement.

Givosiran (ENVISION trial) 3: Monthly SC GalNAc-siRNA targeting ALAS1 (rate-limiting enzyme in heme synthesis). Primary endpoint: annualized attack rate of acute porphyria attacks — 3.2 in givosiran vs. 12.5 in placebo, a 74% reduction (P<0.001).

Lumasiran (ILLUMINATE-A trial) 4: Quarterly or monthly SC GalNAc-siRNA targeting glycolate oxidase (HAO1), reducing hepatic oxalate synthesis. Primary endpoint: least-squares mean difference in change in 24-hour urinary oxalate excretion −53.5 percentage points vs placebo (P<0.001).

Inclisiran (ORION-9 trial — heterozygous FH) 5: Twice-yearly SC GalNAc-siRNA targeting PCSK9 mRNA (n=482 randomized 1:1). Primary endpoint at day 510: LDL-C reduction of 39.7% vs increase of 8.2% in placebo (between-group difference −47.9 percentage points; P<0.001). Inclisiran is notable as an aging-adjacent compound: PCSK9 is cardiovascular risk-relevant, and extremely durable PCSK9 suppression with two injections per year is a plausible cardiovascular aging intervention. It is NOT allele-selective.

Antisense oligonucleotide (ASO) drugs

DrugTargetIndicationFDA approvalPivotal trialMechanismRouteAllele-selective?
Inotersen (Tegsedi)TTR mRNAhATTR amyloidosis with polyneuropathy2018NEURO-TTR 6SC weekly (gapmer)RNase HNo
Nusinersen (Spinraza)SMN2 pre-mRNA (splice-modulation)Spinal muscular atrophy (SMA)2016ENDEAR 7IntrathecalSplice-modulation (steric)No — exon 7 inclusion shift works on all SMN2
Tofersen (Qalsody)SOD1 mRNASOD1-ALS2023 (accelerated)VALOR 8IntrathecalRNase HNo — silences all SOD1
Eteplirsen (Exondys 51)DMD pre-mRNA exon 51Duchenne muscular dystrophy (exon 51-amenable)2016(accelerated approval)Exon-skipping (PMO)IV weeklyNo
Casimersen (Amondys 45)DMD exon 45Duchenne MD (exon 45-amenable)2021—Exon-skipping (PMO)IV weeklyNo
Viltolarsen (Viltepso)DMD exon 53Duchenne MD (exon 53-amenable)2020—Exon-skipping (PMO)IV weeklyNo
Golodirsen (Vyondys 53)DMD exon 53Duchenne MD (exon 53-amenable)2019—Exon-skipping (PMO)IV weeklyNo
Mipomersen (Kynamro)ApoB mRNAFamilial hypercholesterolemia2013; withdrawn 2018—SC weeklyRNase HNo

Inotersen (NEURO-TTR trial) 6: SC weekly gapmer ASO. Primary endpoints (modified NIS+7 and Norfolk QOL-DN) both met. mNIS+7 difference −19.7 points (95% CI −26.4 to −13.0; P<0.001). Dose-limiting toxicities: thrombocytopenia (3 fatal cases during trial) and glomerulonephritis — led to REMS requirement. Thrombocytopenia is the key class-level safety signal for gapmer ASOs.

Nusinersen (ENDEAR trial) 7: Intrathecal steric-blocking ASO redirecting SMN2 splicing to include exon 7. A landmark drug — first neurological oligonucleotide approved. 122 infants enrolled; final analysis n=110 (73 nusinersen, 37 sham). Primary motor-milestone response 51% (37/73) in nusinersen vs. 0% (0/37) in sham control; event-free survival HR=0.53 (P=0.005). Illustrates the potency of splice-modulation for diseases driven by aberrant splicing.

Tofersen (VALOR trial) — critical nuance 8: FDA-approved 2023 via accelerated approval despite the pivotal VALOR trial NOT meeting its primary clinical endpoint. ALSFRS-R change at week 28 was −6.98 (tofersen) vs −8.14 (placebo) in the faster-progression subgroup (difference +1.2 points; P=0.97). Tofersen reduced SOD1 protein in CSF and neurofilament light chain (NfL) in plasma — biomarker evidence of target engagement and neuroprotection — but this did not translate to clinical function improvement over 28 weeks. The FDA accepted biomarker evidence as a basis for accelerated approval. The drug demonstrates that CSF-delivered intrathecal ASOs can successfully silence target mRNA in the CNS, which is mechanistically relevant for future CNS-targeted allele-selective programs. However, the endpoint discordance is a cautionary note.

Mipomersen (Kynamro) — withdrawn: First ASO for hypercholesterolemia; withdrawn from the US market in 2018 due to hepatotoxicity (hepatic fat accumulation) and injection-site reactions outweighing the clinical benefit in an era with better alternatives (PCSK9 inhibitors, inclisiran). Class-precedent value as the first cardiovascular ASO; its withdrawal illustrates the hepatotoxicity risk of PS-backbone ASOs at high doses.

3. Allele-selectivity — research-stage landscape

As of 2026-05-07, no FDA-approved oligonucleotide drug is allele-selective in the strict sense (SNV-discriminating). The research landscape for allele-selective programs includes:

Huntington’s disease (CAG-SNP haplotyping approach): Wave Life Sciences and others have developed siRNA/ASO programs that target HD alleles via linked heterozygous SNPs in cis with the CAG expansion, achieving allele-selective silencing without directly targeting the CAG repeat (which is challenging due to repeat-associated secondary structure). The most recent research (Bragg 2026, Sci Transl Med 9) demonstrates allele-selective ASO targeting of mutant huntingtin intron 1 sequences, improving rescue vs. non-selective approaches in mouse models. Phase 1/2 human trials of allele-selective HD ASOs/siRNAs are ongoing (Wave Life Sciences WVE-003 program).

Polyglutamine diseases: Maeda and colleagues (2026, Mol Ther Nucleic Acids 10) demonstrated an acyclic serinol nucleic acid (SNA)-modified siRNA that selectively silences expanded CAG alleles in polyglutamine disease models (SBMA, SCA3 mouse models), reducing intranuclear aggregation and improving lifespan and motor function while sparing wild-type counterparts. Active research area, no FDA-approved drug.

ALS (SOD1): Tofersen is not allele-selective (it silences all SOD1). A divalent siRNA targeting SOD1 (Weiss 2024, bioRxiv) extended survival in SOD1-G93A mice beyond reported ASO results, with improved CNS penetration — suggesting that next-generation siRNA delivery may surpass current ASO performance for CNS targets. needs-replication (preprint, not peer-reviewed).

4. Aging-relevance — prospective applications

None of the following have clinical programs as of 2026-05-07. These are applications where the class’s mechanism is directly applicable to aging-specific biology.

GNAQ Q209L — cherry angioma

Cherry angiomas are the most common vascular benign skin lesion in aging humans, accumulating from ~40 years of age with near-universal prevalence by 80+. The cause is a somatic gain-of-function SNV: GNAQ Q209L (and less commonly GNAQ R183Q or GNA11 Q209L) in dermal endothelial cells [see cherry-angioma]. The mutant GNAQ protein constitutively activates Gq signalling → PLC-β → PKC → ERK proliferation, driving clonal endothelial expansion.

This is structurally an ideal allele-selective oligonucleotide target:

  • A defined SNV (Q209L: c.626A>T) provides a hybridisation anchor for allele-selective design.
  • The lesion is a localised, accessible tissue (skin) — topical or intralesional delivery bypasses the systemic biodistribution problem that complicates most oligonucleotide programs.
  • The wild-type GNAQ allele should not be silenced (it performs essential signalling functions in endothelial cells).
  • An allele-selective siRNA targeting Q209L mRNA would selectively suppress constitutive Gq signalling in the mutant clone without affecting surrounding wild-type endothelial cells.

No clinical or preclinical published program has been identified targeting GNAQ Q209L with allele-selective siRNA or ASO. needs-replication — a proof-of-concept topical siRNA experiment in a cherry angioma model (or ex vivo human skin) would be the field-opening experiment.

From the perspective of intervention-by-target-immunogenicity: GNAQ Q209L is a Tier 2 target (weakly immunogenic somatic driver, not a neoantigenic frameshift) — allele-selective oligonucleotide is the natural Tier 2 intervention class.

CHIP driver mutations (DNMT3A, TET2, JAK2 V617F)

Clonal hematopoiesis of indeterminate potential (CHIP) involves the age-associated clonal expansion of hematopoietic stem cells carrying somatic driver mutations — most commonly DNMT3A R882H, TET2 loss-of-function, and JAK2 V617F [see clonal-hematopoiesis]. CHIP increases cardiovascular and mortality risk independently of haematologic malignancy.

Allele-selective ASOs targeting mutant DNMT3A R882H or JAK2 V617F transcripts in HSCs would represent a fundamentally different approach to CHIP than current strategies (watchful waiting; cytoreductive therapy for frank MPN). The conceptual challenge: HSC delivery. Current GalNAc-conjugated siRNA platforms achieve excellent hepatic uptake but poor HSC penetration; LNP formulations have some bone marrow distribution but with substantial off-target effects. No clinically validated oligonucleotide delivery strategy for HSCs exists as of 2026. needs-human-replication

PubMed search 2021-2026 for “DNMT3A allele-specific oligonucleotide clonal hematopoiesis” returned zero results; no published programs identified.

Age-associated changes in splicing — altered SR protein levels, reduced SRSF1, changes in U1 snRNP stoichiometry — affect hundreds of transcripts in aged tissues (see splicing-dysregulation if seeded). Splice-correcting ASOs in principle could restore youthful splicing patterns at specific loci. This is distinct from allele-selectivity but uses the same therapeutic class. Speculative; no clinical programs directed at aging splicing.

5. Delivery — the practical bottleneck

Delivery determines biodistribution and fundamentally constrains which aging applications are feasible:

Delivery platformCurrent reachAging application feasibility
GalNAc conjugate (SC injection)Hepatocytes (ASGPR-mediated uptake)Liver-resident aging targets (e.g., PCSK9, TTR, ALAS1 analogs); CHIP liver burden (limited HSC access)
LNP IV infusionLiver predominantly; spleen (ApoE-mediated); lung (ionizable LNP variants)Hepatic targets; some myeloid cell access; IV burden limits chronic dosing
Intrathecal (IT) injectionSpinal cord, brainstem, cortex (ASOs only — CSF distribution)CNS aging targets (TDP-43, α-synuclein, huntingtin); requires lumbar puncture; feasible for serious disease
Topical / intralesionalSkin epidermis and dermis (unmodified siRNA limited; formulation-dependent)Cherry angioma (intralesional) — most accessible aging target in this class
InhaledBronchial epithelium (local), alveolar cells (LNP inhaled)Pulmonary aging targets; not yet clinically developed for ASOs/siRNA
Systemically to HSCsNot yet validated for any oligonucleotide platformCHIP — major delivery gap

Half-life of approved drugs varies by chemistry: GalNAc-siRNA drugs achieve multi-month liver residency (vutrisiran: effective duration ~3 months per dose); gapmer ASOs in CSF have tissue half-lives of weeks (tofersen: 4-week dosing interval after loading). Chronic aging indications would require durable formulations — the GalNAc-siRNA platform’s quarterly dosing is the closest existing template.

6. Safety profile and class limitations

The oligonucleotide class has established safety for monogenic-disease populations. The key class-level signals are:

Phosphorothioate backbone effects: PS backbone substitution (replacing one non-bridging oxygen with sulfur) confers nuclease resistance but also produces non-specific protein binding, contributing to injection-site inflammation, flu-like reactions, and at higher doses, complement activation. Well-managed with current dosing schedules; not a serious safety concern at approved doses.

Thrombocytopenia: Gapmer ASO-specific, particularly for inotersen (NEURO-TTR trial: 3 fatal cases, leading to mandatory platelet monitoring REMS). Mechanism: PS backbone-induced platelet depletion via complement-mediated clearance. Less common with 2’-MOE gapmers at lower doses; not observed with siRNA drugs. Risk management: platelet monitoring; dose adjustments.

Hepatotoxicity: Historical concern with high-dose PS backbone ASOs. Mipomersen withdrawal was partly driven by hepatic steatosis and LFT elevations. Lower-dose GalNAc-targeted siRNA drugs appear hepatically well-tolerated. Tofersen (intrathecal) has no hepatic exposure.

Immunostimulation: Unmethylated CpG motifs in ASO sequences can activate TLR9. Managed by sequence design (CpG-depleted sequences) and chemistry (2’-modifications suppress TLR activation). Not a major clinical problem with current approved drugs.

Kidney: Some ASO platforms show tubular accumulation and proximal tubule vacuolation at high doses. Inotersen had glomerulonephritis signals requiring REMS monitoring.

For aging indications specifically: All approved drugs have been used in seriously ill patient populations with known-high risk tolerance. Aging indications would impose a much lower adverse-event tolerance threshold — particularly for a condition like cherry angioma (cosmetic-adjacent) or CHIP (elevated-but-not-acute risk). This benefit-risk recalibration is the dominant safety consideration for aging translation.

7. Evidence quality summary

DimensionStatus
Pathway conserved in humans?Yes — RNA silencing machinery is human; all approved drugs are human-validated
Phenotype conserved in humans?Yes (for approved indications); prospective aging applications have no human evidence
Replicated in humans?Yes (class — multiple Phase 3 trials); No (aging-specific applications — no trials)

8. Limitations and knowledge gaps

  • No allele-selective oligonucleotide program for any aging-specific somatic mutation exists in clinical development — the class’s aging relevance is entirely prospective. needs-human-replication
  • HSC delivery is unsolved. No oligonucleotide delivery platform achieves adequate HSC uptake for CHIP applications in vivo. This is the dominant translational bottleneck for the most impactful aging target (clonal hematopoiesis). no-mechanism
  • Allele-selectivity in vivo is not yet demonstrated for aging SNVs. SNV-selective discrimination has been shown in HD model systems (CAG-expanded allele vs. normal; or SNP-haplotype-linked programs). Direct translation to small somatic mosaicism SNVs (minor allele fractions often <10%) in aging tissues is unproven. needs-replication
  • Topical/intralesional siRNA formulation maturity for skin delivery is limited. Published data on intradermal delivery of siRNA to dermal endothelium are sparse, though the route is conceptually tractable with lipid-based carriers. No GMP formulation suitable for intralesional cherry angioma use has been described. dose-response-unclear
  • Long-term safety of chronic aging-indication dosing is unknown. Approved drugs are used at defined treatment durations in disease-defined populations. A geroprotective dosing regimen (potentially decades of exposure in otherwise healthy individuals) has no precedent in the class. long-term-unknown
  • Off-target hybridisation: Partial-complementarity matches to non-target transcripts can produce unintended knockdown, particularly for sequences targeting common motifs. Computationally predicted off-target burden grows with genomic sequence complexity. Allele-selective designs must balance SNV discrimination with off-target avoidance.
  • Tofersen’s primary endpoint failure serves as a reminder that CSF biomarker readouts (SOD1 protein, NfL) may not translate to clinical function improvement within trial timeframes — relevant to any CNS aging application where biomarker-to-function translation is uncertain.

9. Cross-references

Footnotes

Footnotes

  1. doi:10.1056/NEJMoa1716153 · Adams D et al. · rct · n=225 (148 patisiran, 77 placebo) · primary endpoint mNIS+7 change: −6.0 ± 1.7 (patisiran) vs +28.0 ± 2.6 (placebo), difference −34.0 points; P<0.001 · model: humans with hATTR amyloidosis with polyneuropathy · NEJM 2018 · archive: pending download (bronze OA) ↩ ↩2

  2. doi:10.1080/13506129.2022.2091985 · Adams D et al. · rct · n=164 (122 vutrisiran, 42 placebo) · primary endpoint mNIS+7 change at 9 months; P=3.54×10⁻¹² · model: humans with hATTR amyloidosis with polyneuropathy · Amyloid 2022 · HELIOS-A trial · archive: pending download (hybrid OA) ↩ ↩2

  3. doi:10.1056/NEJMoa1913147 · Balwani M et al. · rct · n=94 (48 givosiran, 46 placebo) · primary endpoint annualized attack rate: 3.2 (givosiran) vs 12.5 (placebo); 74% reduction (P<0.001) · model: humans with acute intermittent porphyria · NEJM 2020 · ENVISION trial · archive: pending download (bronze OA) ↩ ↩2

  4. doi:10.1056/NEJMoa2021712 · Garrelfs SF et al. · rct · n=39 (26 lumasiran, 13 placebo) · primary endpoint 24-h urinary oxalate change: −53.5 percentage points difference vs placebo (P<0.001); lumasiran group: 65.4% reduction from baseline · model: humans with primary hyperoxaluria type 1 · NEJM 2021 · ILLUMINATE-A trial · archive: download failed (status in archive: failed) ↩ ↩2

  5. doi:10.1056/NEJMoa1913805 · Raal FJ et al. · rct · n=482 randomized 1:1 (inclisiran vs placebo) · primary endpoint LDL-C change at day 510: −39.7% (inclisiran) vs +8.2% (placebo); between-group difference −47.9 percentage points (P<0.001) · model: humans with heterozygous familial hypercholesterolemia · NEJM 2020 · ORION-9 trial · archive: pending download (bronze OA) ↩ ↩2

  6. doi:10.1056/NEJMoa1716793 · Benson MD et al. · rct · n=173 randomized (CT.gov NCT01737398); 172 received at least one dose (112 inotersen, 60 placebo) · primary endpoint mNIS+7 difference −19.7 points (95% CI −26.4 to −13.0); P<0.001; Norfolk QOL-DN difference −11.7 (P<0.001) · model: humans with hATTR amyloidosis with polyneuropathy · NEJM 2018 · NEURO-TTR trial; thrombocytopenia REMS required · archive: pending download (bronze OA) ↩ ↩2

  7. doi:10.1056/NEJMoa1702752 · Finkel RS et al. · rct · n=122 enrolled (CT.gov NCT02193074); final analysis n=110 (73 nusinersen, 37 sham) · primary endpoint motor-milestone response: 51% (37/73) nusinersen vs 0% (0/37) sham; event-free survival HR=0.53 (P=0.005) · model: human infants with SMA type 1 · NEJM 2017 · ENDEAR trial · archive: pending download (bronze OA) ↩ ↩2

  8. doi:10.1056/NEJMoa2204705 · Miller TM et al. · rct · n=108 (72 tofersen, 36 placebo) · primary endpoint ALSFRS-R change at 28 weeks: −6.98 (tofersen) vs −8.14 (placebo), difference +1.2 points (P=0.97) — primary endpoint NOT met; CSF SOD1 protein and plasma NfL significantly reduced (biomarker endpoints met); FDA accelerated approval 2023 on biomarker basis · model: humans with SOD1-ALS · NEJM 2022 · VALOR trial · archive: pending download (bronze OA) ↩ ↩2

  9. doi:10.1126/scitranslmed.adv0702 · Bragg RM, Landles C, Smith EJ, Osborne GF, Mathews EW, Cantle JP, Bates GP, Carroll JB · in-vivo (mouse; HttQ111 heterozygous knockin) · PMID 41849580 · allele-selective ASO targeting mutant huntingtin intron 1 reduces mutant full-length HTT and HTT1a; eliminates aggregate formation and provides marked transcriptional protection vs. non-selective pan-allele ASO · Sci Transl Med 2026 Mar 18;18(841):eadv0702 ↩

  10. doi:10.1016/j.omtn.2025.102802 · Maeda K, Hirunagi T, Sahashi K, Kamiya Y et al. (Katsuno M senior) · in-vivo (mouse SBMA and SCA3 models) + in-vitro · PMID 41552385 · acyclic serinol nucleic acid (SNA)-modified siRNA targeting CAG repeats selectively silences expanded polyQ alleles without affecting wild-type; reduces intranuclear aggregation in SBMA/SCA3 mice; improves lifespan and motor function in SBMA mice · Mol Ther Nucleic Acids 2026 Mar 12;37(1):102802 · PMCID: PMC12804371 ↩

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