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Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates
Open accessPublished version of a preprint
Abstract
Therapeutics based on short interfering RNAs (siRNAs) delivered to hepatocytes have been approved, but new delivery solutions are needed to target additional organs. Here we show that conjugation of 2'-O-hexadecyl (C16) to siRNAs enables safe, potent and durable silencing in the central nervous system (CNS), eye and lung in rodents and non-human primates with broad cell type specificity. We show that intrathecally or intracerebroventricularly delivered C16-siRNAs were active across CNS regions and cell types, with sustained RNA interference (RNAi) activity for at least 3 months. Similarly, intravitreal administration to the eye or intranasal administration to the lung resulted in a potent and durable knockdown. The preclinical efficacy of an siRNA targeting the amyloid precursor protein was evaluated through intracerebroventricular dosing in a mouse model of Alzheimer's disease, resulting in amelioration of physiological and behavioral deficits. Altogether, C16 conjugation of siRNAs has the potential for safe therapeutic silencing of target genes outside the liver with infrequent dosing.
Overview
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Written from the paper’s full text.
TL;DR
Conjugating 2'-O-hexadecyl (C16) to chemically stabilized siRNAs enables potent, durable RNAi silencing in the CNS, eye, and lung after local administration in rodents and nonhuman primates. The platform supports infrequent dosing and candidate selection for extrahepatic clinical trials.
Key findings
- In rats, C16-siRNA with 5'-VP and 2'-O-C16 at sense-strand N6 produced up to 90% SOD1 knockdown in spinal cord and up to 75% in brain after a single 0.9 mg intrathecal (IT) dose; there was no activity in striatum, liver, or kidney at the tested dose and time point. Brain regions showed >75% silencing for at least 3 months, lower spinal cord out to 6 months, and the frontal cortex siRNA half-life for the 0.9 mg group was calculated at 3–4 months.
- In nonhuman primates (NHPs), APP-targeting C16-siRNA with both 5'-VP and 2'-O-C16 after a single 60 mg IT dose gave up to 70% APP knockdown in spinal cord and up to 80% in brain, including 25% in deep brain striatum, at 3 months; CSF soluble APP knockdown was >75% for 3 months, recovered to 50% at 4.5 months, and fully recovered by 9 months in most animals. No activity was seen in NHP liver or kidney at 3 months after 60 mg IT.
- In NHP eye, a single intravitreal TTR-targeting C16-siRNA dose sustained >80% aqueous humor TTR knockdown out to 6 months at 100 or 300 μg/eye; at 3 μg/eye, TTR protein remained reduced by 77% at 1 month, and RPE TTR mRNA knockdown was >95% at 100 and 300 μg/eye at 6 months. An unconjugated siRNA showed no knockdown at 10 μg/eye and only 33% at 30 μg/eye at 1 month, versus 81% for the C16 conjugate at 10 μg/eye.
- In mouse lung, intranasal SOD1 C16-siRNA at 10 mg/kg reduced whole-lung SOD1 mRNA by 62–78% in the first month and by 57% at 2 months; doses of 0.3, 1, 3, or 10 mg/kg gave 57%, 53%, 71%, and 68% reductions at day 10, while a single intravenous 30 mg/kg dose reduced SOD1 mRNA by 42% at day 10.
Methods
- Oligonucleotides were synthesized with 2'-F, 2'-O-methyl, phosphorothioate, GNA, 5'-(E)-vinylphosphonate, and 2'-O-C16 phosphoramidites, then purified and annealed into siRNAs.
- In vivo studies used rat IT lumbar puncture (0.07, 0.3, or 0.9 mg; repeat 0.3 mg monthly), NHP IT (45 or 60 mg), NHP intravitreal injection (3, 10, 30, 100, or 300 μg/eye), and mouse intranasal or intravenous dosing; tissues, CSF, and aqueous humor were collected at indicated time points.
- Main analyses included RT-qPCR with the ΔΔCt method for target mRNA normalized to housekeeping genes, ELISA/MSD for TTR and soluble APP proteins, LC-HRMS for siRNA quantitation, and IHC/ISH plus histopathology for distribution, cell-type uptake, and safety.
Limitations
- Stated: the precise mechanism by which 2'-O-C16 promotes intracellular delivery is under investigation; only a small fraction (<5%) of C16-siRNA is retained in the CNS after IT administration; no concurrent vehicle controls were tested in the NHP CNS safety assessment; IT administration success varied, contributing to exposure variability; oligodendrocyte uptake was below IHC detection; and alveolar activity could not be assessed because SOD1 is only expressed in large airways.
- Evident from the text: the findings are nonclinical, using rodents and NHPs, with no human efficacy or safety data; several NHP groups had small sample sizes (N=1–4 per group); and activity was absent in some regions or organs at the tested dose levels and time points, such as rat striatum, liver, and kidney.
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Claims the paper makes
61 Own result · 7 Own method · 5 Partly supported · 4 Own interpretation · 4 No basis given · 2 No full text of the sources · 1 Supported so far · accuracy not yet measured
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Next, we evaluated other siRNA design elements and con rmed that full chemical modi cation with strategic placement of 2'-uoro and 2'-O-methyl modi cations 9 is required for robust siRNA activity in the CNS.”
What the sources say
- Partly supportedcites [9] Foster, D. J. et al. Advanced siRNA designs further improve in vivo performance of GalNAc-siRNA conjugates. Mol. Ther. 26, 708–717 (2018). sourceExperimental — accuracy not yet measured
The Introduction and Results (page unavailable) describe fully 2′-F/2′-OMe-modified GalNAc-siRNAs and show that modification placement affects activity. But the in vivo experiments measured silencing in liver, not the CNS, and the paper does not establish that full chemical modification is required for robust CNS activity. (LLM, conf=0.88)
boosteddirect- Asserted: passes — The authors put it forward as true.
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- Partly supported
The sources with a verdict support this claim; the rest weren’t checked yet, have no full text we could read, or their verdicts aren’t rated yet.
In the paper
“Furthermore, the ESC+ chemistry employing glycol nucleic acid (GNA) in the antisense seed region for increased speci city 10,30 retained activity in rat two weeks after a single 0.9 mg IT dose (Fig. 1d).”
What the sources say
- Supportedcites [10] Janas, M. M. et al. Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity. Nat. Commun. 9, 723 (2018). source
The Results section, “Impact of destabilizing seed-mediated off-target binding” (page not available), reports that GNA in the antisense seed region reduced off-target effects while maintaining on-target activity. The citation supports that chemistry and specificity point; the rat intrathecal-dose result is attributed to the citing paper’s Fig. 1d, not to this source. (LLM, conf=0.90)
- Not checked — no full text of the sourcecites [30] Hall, H. et al. Magnetic resonance spectroscopic methods for the assessment of metabolic functions in the diseased brain. Curr. Top. Behav. Neurosci. 11, 169–198 (2012). source
plaindirectSingle case- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here we report that conjugation of 2'-O-hexadecyl (C16) to siRNAs enables e cient silencing in the central nervous system (CNS), eye, and lung of multiple nonclinical species with broad cell type speci city.”
plaindirect- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“There was no activity in the rat striatum, liver, and kidney at the tested dose level and time point.”
plain- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At one month post a single IT dose of 0.07 mg, 0.3 mg, or 0.9 mg, dose dependent SOD1 knockdown was observed in the spinal cord and the brain (Fig. 2c).”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The dose-exposure relationship of the SOD1 C16-siRNA could be characterized across all dose levels explored with a rst-order pharmacokinetic model.”
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Similarly, intravitreal and intranasal administration of C16-siRNAs resulted in potent and sustained knockdown in the eye and lung, respectively.”
- Also stated in: § Introduction · boosted
“We also demonstrate that the C16-siRNA platform enables durable silencing after IVT delivery into the eye and via IN delivery into the lung.”
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Consistent with positive siRNA IHC results, robust knockdown by RT-qPCR was observed in neurons, astrocytes, and microglia (Fig. 2b).”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Only minimal SOD1 knockdown was detected in liver or kidney under these conditions.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Frontal cortex exposure was generally linear with increasing dose at all time points evaluated.”
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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- Probably not a substantial claim. 10
- It may state two separate claims as one. 29
- The quote only partly states this claim. 1
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“For liver targets, lipid nanoparticles (LNPs) and N-acetylgalactosamine (GalNAc) conjugates are two clinically validated delivery strategies, with multiple regulatory approvals that include Onpattro® (patisiran) 2,3 , Givlaari® (givosiran) 4 , Oxlumo® (lumaisran) 5 , and Leqvio® (inclisiran) [6][7][8] , and numerous additional programs in various stages of clinical development across several thera”
What the sources say
- Partly supportedcites [2] Adams, D. et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N. Engl. J. Med. 379, 11–21 (2018). sourceExperimental — accuracy not yet measured
The paper’s introduction describes patisiran as a hepatically directed RNAi therapeutic, and the Results report benefit in a phase 3 trial, supporting its use as a clinical example for a liver target. But our copy calls patisiran investigational and does not identify its delivery system as a lipid nanoparticle or report regulatory approval. The citation is attached to Onpattro (patisiran), not to the other named drugs. (LLM, conf=0.84)
- Not checked — no full text of the sourcecites [3] Kristen, A. V. et al. Patisiran, an RNAi therapeutic for the treatment of hereditary transthyretin-mediated amyloidosis. Neurodegener. Dis. Manag. 9, 5–23 (2019). source
- Supportedcites [4] Balwani, M. et al. Phase 3 trial of RNAi therapeutic givosiran for acute intermittent porphyria. N. Engl. J. Med. 382, 2289–2301 (2020). source
This citation is attached to Givlaari (givosiran), not to the other listed drugs. The paper says givosiran uses a GalNAc conjugate for targeted delivery to hepatocytes and reports its FDA and EMA approvals (Discussion). (LLM, conf=0.93)
- Partly supportedcites [5] Garrelfs, S. F. et al. Lumasiran, an RNAi therapeutic for primary hyperoxaluria type 1. N. Engl. J. Med. 384, 1216–1226 (2021). sourceExperimental — accuracy not yet measured
The Results identify lumasiran as a liver-directed RNAi therapeutic, and the Discussion reports substantial oxalate reductions in its phase 3 trial, supporting its use as a clinically studied example. This citation is attached to the lumasiran example, not the other named drugs. Our copy does not identify lumasiran as a GalNAc conjugate or state that Oxlumo received regulatory approval; it calls lumasiran investigational. (LLM, conf=0.84)
plain- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“The naturally occurring RNAi pathway can also be harnessed in extrahepatic organs by building on nearly two decades of efforts on liver siRNA design optimization [9][10][11][12] ; however, novel delivery approaches are needed.”
What the sources say
- Partly supportedcites [9] Foster, D. J. et al. Advanced siRNA designs further improve in vivo performance of GalNAc-siRNA conjugates. Mol. Ther. 26, 708–717 (2018). sourceExperimental — accuracy not yet measured
The Introduction states that synthetic siRNAs harness the endogenous RNAi pathway and describes targeted delivery to hepatocytes; the Discussion describes further optimization of siRNA designs. The paper does not establish that these designs can be used in extrahepatic organs or state that novel delivery approaches are needed for them. No page numbers are available in our copy. (LLM, conf=0.85)
- Partly supportedcites [10] Janas, M. M. et al. Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity. Nat. Commun. 9, 723 (2018). sourceExperimental — accuracy not yet measured
The Introduction (page unavailable) says exogenous siRNAs can harness the natural RNAi pathway and describes chemical modifications and GalNAc-mediated delivery to hepatocytes. It does not address harnessing RNAi in extrahepatic organs, establish nearly two decades of liver siRNA design optimization, or say that novel delivery approaches are needed for those organs. (LLM, conf=0.85)
- Partly supportedcites [11] Nair, J. K. et al. Impact of enhanced metabolic stability on pharmacokinetics and pharmacodynamics of GalNAc-siRNA conjugates. Nucleic Acids Res. 45, 10969–10977 (2017). sourceExperimental — accuracy not yet measured
The Introduction describes advances in siRNA design and chemistry and explains how GalNAc conjugation enables delivery to the liver. It does not establish a nearly two-decade period of liver optimization or address whether those designs can be applied to extrahepatic organs. The statement that novel delivery approaches are needed follows the citation rather than being directly attributed to it. (LLM, conf=0.82)
plainconditional- Asserted: passes — The authors put it forward as true.
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- Partly supported
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In the paper
“2'-O-C16 was well tolerated across both strands, with potency similar to the unconjugated siRNA, except for a few positions known to be sensitive to sterically demanding 2'-modi cations 9 .”
What the sources say
- Partly supportedcites [9] Foster, D. J. et al. Advanced siRNA designs further improve in vivo performance of GalNAc-siRNA conjugates. Mol. Ther. 26, 708–717 (2018). sourceExperimental — accuracy not yet measured
The Introduction and Results describe how sterically demanding 2′ modifications can reduce RNAi activity at particular positions in the sense and antisense strands. But the paper examines 2′-OMe and 2′-F, not 2′-O-C16; it does not establish that 2′-O-C16 was tolerated across both strands or had potency similar to unconjugated siRNA. Page numbers are unavailable in our copy. (LLM, conf=0.79)
plain- Asserted: passes — The authors put it forward as true.
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- Partly supported
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In the paper
“Additionally, off-target mitigation strategies involving placing a thermally destabilizing modi cation such as GNA in the antisense strand seed region 10 also performed well, thus allowing for translation of safety improvements with the ESC+ platform beyond liver.”
What the sources say
- Partly supportedcites [10] Janas, M. M. et al. Selection of GalNAc-conjugated siRNAs with limited off-target-driven rat hepatotoxicity. Nat. Commun. 9, 723 (2018). sourceExperimental — accuracy not yet measured
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Dose dependent silencing in the frontal cortex corresponded with drug exposure through the 0.07 mg, 0.3 mg, and 0.9 mg groups (Fig. 2f), with the siRNA half-life for the 0.9 mg group calculated to be three to four months.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“APP siRNAs, with or without 5'-VP on the antisense strand and/or sense N6 2'-O-C16 conjugation, were well-tolerated and there were no test item-related microscopic ndings in the examined brain, spinal cord, and dorsal root ganglia sections.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Nadir of knockdown was observed as early as one week post-dose (earliest time point tested), with sustained >75% APP silencing for three months post-dose.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“One month after a single 0.9 mg IT dose, most tested positions provided activity equivalent to sense strand N6 (Fig. 1c), con rming tolerance of 2'-O-C16 modi cation at multiple positions of the siRNA sense strand.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Intrathecally delivered C16-siRNAs are active across CNS regions and cell types, with sustained silencing for at least three months, which is an especially important outcome considering the challenging dosing route.”
- Also stated in: § Introduction · hedged
“Our results indicate that C16-siRNAs administered via a clinically feasible intrathecal (IT) route of administration have durable activity across CNS regions and cell types, with a favorable nonclinical safety pro le to date.”
plaindirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The intrathecal route of administration is clinically feasible.
- Also stated in: § Introduction · hedged
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Consistent with the rat data, siRNA containing both 5'-VP and 2'-O-C16 had the best activity across CNS regions, with up to 70% APP knockdown in the spinal cord and up to 80% in the brain, including 25% knockdown in deep brain (striatum).”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Silencing appeared to be additive with 88%, 85%, and 81% silencing observed in frontal cortex, cerebellum, and thoracic spinal cord, respectively, at 1 month after three 0.3 mg doses, compared to 85%, 82%, and 82% in those regions at the same time point following a single 0.9 mg dose (Fig. 2d).”
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In the paper
“APP knockdown recovered to 50% at 4.5 months, with full recovery at nine months in most animals as assessed by CSF protein biomarkers.”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“In the lower spinal cord, the maximal level of target knockdown was observed as early as one week post-dose (earliest time point tested), with sustained silencing out to six months.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Following a single IT dose of 60 mg, an unconjugated siRNA lacking 2'-O-C16 as well as 5'-VP had minimal activity in the spinal cord and no activity in the brain at three months post-dose (Fig. 3a).”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The siRNA combining both 5'-VP and 2'-O-C16 had the best activity across CNS regions, with up to 90% SOD1 knockdown in the spinal cord and up to 75% in the brain.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“IHC also revealed siRNA in vascular endothelium and perivascular macrophages (data not shown), which was shown to be nonfunctional by RT-qPCR (Fig. 2b).”
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“Addition of 5'-VP to the antisense strand or internal 2'-O-C16 conjugation at N6 of the sense strand produced knockdown in the spinal cord (up to 60% APP lowering), but only modest activity in the brain (up to 30% APP lowering) at three months post-dose.”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“RNAi activity in the CNS generally increased with lipid chain length, with 2'-O-C16 providing optimal activity in the rat spinal cord and brain at two weeks after a single IT dose of 0.9 mg (Fig. 1a).”
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Fortuitously, the variability in delivery allowed us to observe a robust exposure response relationship, which was conserved across these tissues.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Notably, higher concentrations of C16-siRNA and greater silencing were observed in prefrontal cortex and thoracic spinal cord than in the deep brain region of the striatum.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Evidence of accumulation was observed in this tissue following repeat doses, with the siRNA exposure following the third monthly 0.3 mg dose similar to a single 0.9 mg dose, and additive accumulation observed following the fourth and fth doses.”
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Brain regions showed >75% silencing for at least three months with partial recovery out to six months, except for temporal cortex where SOD1 knockdown started to recover at two months post-dose.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The addition of either 5'-VP to the antisense strand or internal 2'-O-C16 conjugation at sense strand N6 produced robust knockdown in the spinal cord (up to 80% SOD1 mRNA lowering), but only modest knockdown in the brain (up to 50% SOD1 mRNA lowering).”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Doses of 0.3, 1, 3, or 10 mg/kg by IN injection resulted in SOD1 mRNA reductions of 57%, 53%, 71%, and 68%, respectively, while a single intravenous (IV) injection at 30 mg/kg reduced SOD1 mRNA by 42% at the same day ten timepoint (Fig. 5e).”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here we report for the rst time a systematic evaluation of lipophiles of varying lengths and siRNA design features to identify an optimal conjugate with 2'-O-C16 that enables widespread siRNA distribution in the spinal cord and brain following administration into rodent and NHP CSF via a clinically feasible IT dosing route, with no safety signals observed in our studies.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The intrathecal route of administration is clinically feasible.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“SOD1 mRNA in lung was reduced by 62%-78% in the rst month, with sustained activity out to two months post-dose with 57% mRNA lowering.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Within the affected areas, there were minimal decreases in Luxol Fast Blue (LFB) staining intensity and a minimal increase in the number of IBA-1 positive microglia.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The same conjugation strategy also enables broad siRNA distribution and durable activity in the eye and lung after local delivery.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“At one month, aqueous humor TTR protein levels in animals treated with the unconjugated siRNA showed no knockdown at the 10 μg/eye dose and a modest 33% knockdown at the 30 μg/eye dose, compared to 81% knockdown observed for the 2'-O-C16 conjugate at 10 μg/eye (Fig. 4d).”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“RNA interference (RNAi) therapeutics utilize an endogenous mechanism whereby short interfering RNAs (siRNAs) direct the RNA-induced silencing complex (RISC) to target gene transcripts, resulting in a sequence-speci c and catalytic RNA cleavage and subsequent lowering of the target protein 1 .”
What the sources say
- Not checked — no full text of the sourcecites [1] Setten, R. L., Rossi, J. J. & Han, S. P. The current state and future directions of RNAi-based therapeutics. Nat. Rev. Drug Discov. 18, 421–446 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Proper placement of the needle was con rmed via CSF back ow in the hub of the needle.”
plaindirect- Asserted: fails — The authors may not put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. The quote only partly states this claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Intravitreal injections were performed by a board-certi ed veterinary ophthalmologist.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Standards and samples were added to the plate, 100 µL/well, in duplicate and incubated for 2 hours at room temperature with shaking at 600 rpm.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“H&E based microscopic ndings were recorded in the Pristima v7.0.0 System (Xybion, NJ) and graded on a scale of 1-5, (1=minimal, 2= mild, 3=moderate, 4=marked, and 5=severe) by a board-certi ed veterinary pathologist.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“All studies were conducted using protocols consistent with local, state and federal regulations, as applicable, and approved by the Institutional Animal Care and Use Committee (IACUC) at Alnylam Pharmaceuticals, Charles River Laboratories (CRL), or LabCorp (formerly Covance, Inc.), as applicable.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Proper placement of the needle was con rmed via CSF back ow in the hub of the needle.”
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The identities and purities of all oligonucleotides were con rmed using ESI-LC/MS and IEX HPLC, respectively.”
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The intrathecal route of administration is clinically feasible.
“Our results indicate that C16-siRNAs administered via a clinically feasible intrathecal (IT) route of administration have durable activity across CNS regions and cell types, with a favorable nonclinical safety pro le to date.”
“Here we report for the rst time a systematic evaluation of lipophiles of varying lengths and siRNA design features to identify an optimal conjugate with 2'-O-C16 that enables widespread siRNA distribution in the spinal cord and brain following administration into rodent and NHP CSF via a clinically feasible IT dosing route, with no safety signals observed in our studies.”
The paper relies on this without support.
SOD1 is only expressed in large airways.
“We were not able to assess activity in the alveoli since SOD1 is only expressed in large airways.”
The paper relies on this without support.
Durability of silencing in nonclinical species predicts infrequent dosing in humans.
“The sustained knockdown observed may allow for bi-annual or even less frequent dosing of C16-siRNAs in humans, which is an important consideration due to the challenging nature of IT or IVT dosing.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source doesn’t support the claim as written.
In the citing paper
“For example, unconjugated siRNA structures administered carrier-free into CSF penetrate throughout the CNS but are not sufficiently internalized by cells to achieve potent gene silencing [8].”
From Elucidating brain transport pathways and cell type-dependent gene silencing of a durable lipid–siRNA conjugate administered into cerebrospinal fluid (2025) · cites this paper as [8]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe cited source doesn’t support the claim as written.
In the citing paper
“For example, unconjugated siRNA structures administered carrier-free into CSF are able to disperse homogenously into the CNS but are not sufficiently internalized by cells to achieve sustained gene silencing.22”
From Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system (2024) · cites this paper as [22]
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, the delivery of mRNA to the brain remains a formidable challenge due to the blood–brain barrier (BBB)18,19.”
From Blood–brain-barrier-crossing lipid nanoparticles for mRNA delivery to the central nervous system (2025) · cites this paper as [19]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“vinyl phosphonate was integrated at the 5′ antisense position, which is an important feature for maximal silencing in the CNS [8,22].”
From Elucidating brain transport pathways and cell type-dependent gene silencing of a durable lipid–siRNA conjugate administered into cerebrospinal fluid (2025) · cites this paper as [8]
The cited source says what the claim attributes to it.
In the citing paper
“Notably, C16-siRNA did not achieve knockdown in the striatum of rats, and the divalent siRNA was not effective throughout the striatum of Dorset sheep.22,49”
From Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system (2024) · cites this paper as [22]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Notably, C16-siRNA did not achieve knockdown in the striatum of rats, and the divalent siRNA was not effective throughout the striatum of Dorset sheep.22,49”
From Lipid-siRNA conjugate accesses a perivascular transport mechanism and achieves widespread and durable knockdown in the central nervous system (2024) · cites this paper as [22]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Additional information
“was administered as a single intravitreal (IVT) injection to cynomolgus monkeys at 60 mg at 3, 30, 100 or 300 μg/eye.”
§ C16 conjugation enables e cient siRNA delivery to the eye
“A single IVT dose of this siRNA showed dose-dependent lowering of TTR in the aqueous humor, with sustained >80% knockdown out to six months at the dose of 100 or 300 μg/eye (Fig. 4a).”
Citations
Cites
Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis
Adams, D., Gonzalez-Duarte, A., O’Riordan, W. D., Yang, C.-C., Ueda, M., Kristen, A. V., Tournev, I., Schmidt, H. H., Coelho, T., Berk, J. L., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1716153 · Cited by 3,047
Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy
Finkel, R. S., Mercuri, E., Darras, B. T., Connolly, A. M., Kuntz, N. L., Kirschner, J., Chiriboga, C. A., Saito, K., Servais, L., Tizzano, E., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1702752 · Cited by 2,337
Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol
Ray, K. K., Wright, R. S., Kallend, D., Koenig, W., Leiter, L. A., Raal, F. J., Bisch, J. A., Richardson, T., Jaros, M., Wijngaard, P. L. J., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1912387 · Cited by 1,665
The current state and future directions of RNAi-based therapeutics
Setten, R. L., Rossi, J. J., & Han, S.-P. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0017-4 · Cited by 1,443
Nair, J. K., Willoughby, J. L. S., Chan, A., Charisse, K., Alam, M. R., Wang, Q., Hoekstra, M., Kandasamy, P., Kel’in, A. V., Milstein, S., et al. (2014) · Journal of the American Chemical Society · doi:10.1021/ja505986a · Cited by 1,141
Self-citationInclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol
Ray, K. K., Landmesser, U., Leiter, L. A., Kallend, D., Dufour, R., Karakas, M., Hall, T., Troquay, R. P. T., Turner, T., Visseren, F. L. J., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1615758 · Cited by 992
Mechanisms and optimization of in vivo delivery of lipophilic siRNAs
Wolfrum, C., Shi, S., Jayaprakash, K. N., Jayaraman, M., Wang, G., Pandey, R. K., Rajeev, K. G., Nakayama, T., Charrise, K., Ndungo, E. M., et al. (2007) · Nature Biotechnology · doi:10.1038/nbt1339 · Cited by 974
Self-citationInclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia
Raal, F. J., Kallend, D., Ray, K. K., Turner, T., Koenig, W., Wright, R. S., Wijngaard, P. L. J., Curcio, D., Jaros, M. J., Leiter, L. A., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1913805 · Cited by 818
Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria
Balwani, M., Sardh, E., Ventura, P., Peiró, P. A., Rees, D. C., Stölzel, U., Bissell, D. M., Bonkovsky, H. L., Windyga, J., Anderson, K. E., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1913147 · Cited by 608
Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1
Garrelfs, S. F., Frishberg, Y., Hulton, S. A., Koren, M. J., O’Riordan, W. D., Cochat, P., Deschênes, G., Shasha-Lavsky, H., Saland, J. M., van’t Hoff, W. G., et al. (2021) · New England Journal of Medicine · doi:10.1056/nejmoa2021712 · Cited by 531
Research works printed but not linked: 1
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Cited by
Sorted by citations
Items 101–200 of 259
Harnessing antiviral RNAi therapeutics for pandemic viruses: SARS-CoV-2 and HIV
Bowden-Reid, E., Moles, E., Kelleher, A. D., & Ahlenstiel, C. (2025) · Drug Delivery and Translational Research · doi:10.1007/s13346-025-01788-x · Cited by 15
“In addition to GalNAc and LNPs, other nanocarriers for siRNA delivery currently explored in clinical trials include polymeric [78, 181], inorganic [182] and lipid-based nanoparticles [183–185], exosomes [186] and conjugates [46, 187, 188] (Fig.”
Cholesterol Conjugates of Small Interfering RNA: Linkers and Patterns of Modification
Chernikov, I. V., Ponomareva, U. A., Meschaninova, M. I., Bachkova, I. K., Vlassov, V. V., Аркадьевна, З. М., & Chernolovskaya, E. L. (2024) · Molecules · doi:10.3390/molecules29040786 · Cited by 10
“Folate [8], carbohydrates [9,10], cholesterol [11], aptamers [12], peptides [13,14], antibodies [15], lipids, and aliphatic chains of varying lengths [16] have been used for the attachment to siRNA [7,17].”
BackgroundCombinatorial Synthesis of Alkyl Chain‐Capped Poly(β‐Amino Ester)s for Effective siRNA Delivery
Chen, B., Ren, Q., Jiang, P., Wu, Q., Shuai, Q., & Yan, Y. (2024) · Macromolecular Bioscience · doi:10.1002/mabi.202400168 · Cited by 11
Ravichandiran, V., Kesharwani, A., Anupriya, Bhaskaran, M., Parihar, V. K., Bakhshi, S., Velayutham, R., & Kumarasamy, M. (2024) · Precision medicine and engineering. · doi:10.1016/j.preme.2024.100010 · Cited by 11
Albumin-binding RNAi Conjugate for Carrier Free Treatment of Arthritis
Colazo, J. M., Hoogenboezem, E. N., Keech, M. C., Francini, N., Shah, V., Yu, F., Lo, J. H., Sorets, A. G., McCune, J. T., Cho, H., et al. (2023) · doi:10.1101/2023.05.31.542971 · Cited by 11
Chemical strategies for brain delivery of genomic therapy
Li, H., Yu, C., Markovic, T., Nestler, E. J., & Dong, Y. (2025) · Nature Reviews Chemistry · doi:10.1038/s41570-025-00770-y · Cited by 16
Li, L., Wang, Y., Meng, J., Wang, X., Wu, X., Wo, Y., Shang, Y., & Zhang, Z. (2024) · Journal of Nanobiotechnology · doi:10.1186/s12951-024-03003-4 · Cited by 11
RNAi-mediated rheostat for dynamic control of AAV-delivered transgenes
Subramanian, M. P., McIninch, J., Zlatev, I., Schlegel, M. K., Kaittanis, C., Nguyen, T. M., Agarwal, S., Racie, T., Alvarado, M. A., Wassarman, K., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-37774-5 · Cited by 11
Self-citationLi, Y., Zhang, J., Ma, B., Yu, W., Xu, M., Luan, W., Yu, Q., Zhang, L., Rong, R., Fu, Y., et al. (2024) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2024.124786 · Cited by 10
Angleró-Rodríguez, Y., Lempp, F. A., Subramanian, M. P., McIninch, J., Schlegel, M. K., Bohan, D., Wong, E. Y. M., Brown, C. R., Foster, D. J., Castoreno, A. B., et al. (2024) · Nucleic Acids Research · doi:10.1093/nar/gkae1195 · Cited by 10
“In previous studies using other C16-siRNAs, we have reported 56 days of sustained silencing of an endogenous lung target in rodents ( 10 ).”
InfluentialSelf-citationFeng, D., Fan, X., Hu, Y., et al. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c01739 · Cited by 9
Bioconjugates for improved delivery of oligonucleotide therapeutics to the central nervous system
Lee, H. J., Xie, Y., Greineder, C. F., & Tessier, P. M. (2026) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2026.115778 · Cited by 11
Identification of selective and non-selective C9ORF72 targeting in vivo active siRNAs
Gilbert, J. W., Kennedy, Z., Godinho, B. M. D. C., Summers, A., Weiss, A., Echeverria, D., Bramato, B. M., McHugh, N., Cooper, D., Yamada, K., et al. (2024) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2024.102291 · Cited by 8
Self-citationStrnad, P., & Martín, J. S. (2023) · Expert Opinion on Investigational Drugs · doi:10.1080/13543784.2023.2239707 · Cited by 9
“the central nervous system (CNS), eye and lung in rodents and non-human primates [39].”
BackgroundCerebral Amyloid Angiopathy: Clinical Presentation, Sequelae and Neuroimaging Features—An Update
Weidauer, S., & Hattingen, E. (2025) · Biomedicines · doi:10.3390/biomedicines13030603 · Cited by 11
“However, lipophilic short-interfering ribonucleic acids (RNAs) and stimulation-induced entrainment of neurovascular oscillations might reflect promising new therapeutic approaches [128,129].”
Ye, J., Suizu, F., Yamakawa, K., Mukai, Y., Yoneyama, H., Kondo, J., Kato, M., Nishiyama, A., Yahagi, N., & Kadota, K. (2024) · Molecular Therapy Oncology · doi:10.1016/j.omton.2024.200812 · Cited by 8
Strategic deactivation of mRNA COVID‐19 vaccines: New applications for siRNA therapy and RIBOTACs
Hulscher, N., McCullough, P. A., & Marotta, D. E. (2024) · The Journal of Gene Medicine · doi:10.1002/jgm.3733 · Cited by 9
“101 These developments significantly expand the potential of RNAi therapeutics to treat a wide range of diseases and conditions, including those caused by persistent S protein production from mRNA vaccines.”
Chernikov, I. V., Ponomareva, U. A., Meschaninova, M. I., Bachkova, I. K., Teterina, A. A., Gladkikh, D. V., Savin, I. A., Vlassov, V. V., Аркадьевна, З. М., & Chernolovskaya, E. L. (2023) · Nucleic Acid Therapeutics · doi:10.1089/nat.2023.0051 · Cited by 8
Hariharan, V. N., Nakamura, T., Shin, M., Tang, Q., Sontakke, V. A., Caiazzi, J., Hildebrand, S. R., Khvorova, A., & Yamada, K. (2024) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2024.102230 · Cited by 7
“3,10 Interestingly, the distribution pro fi les of siRNA conjugated to lipids with similar hydrophobicity (based on retention time in a reverse-phase high-performance liquid chromatography [HPLC] column) were different, indicating that other properties of the lipid conjugate in addition to…”
Advances in locally administered nucleic acid therapeutics
Shen, J., Duan, X., Xie, T., Zhang, X., Cai, Y., Pan, J., Zhang, X., & Sun, X. (2025) · Bioactive Materials · doi:10.1016/j.bioactmat.2025.02.043 · Cited by 8
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Self-citationADARs: pleiotropy in function, versatility in application
Zhang, Y., Bryant, J., Herron, L., & Mali, P. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf672 · Cited by 9
Chemical Modifications in Nucleic Acid Therapeutics
Lennox, K. A., Young, R. C., & Behlke, M. A. (2025) · Methods in molecular biology · doi:10.1007/978-1-0716-4742-4_3 · Cited by 8
RNA Therapies in Cardio-Kidney-Metabolic Syndrome: Advancing Disease Management
Mohammadi, A., Karimian, A., Shokri, K., Mohammadi, A., Karzar, N. H., Bahar, R., Radfar, A., Pakyari, M., & Tehrani, B. N. (2025) · Journal of Cardiovascular Translational Research · doi:10.1007/s12265-025-10603-4 · Cited by 7
“Additionally, assessing tissue-specific drug targeting, long-term organ safety, and immunogenicity of delivery vehicles is crucial, especially in chronic conditions requiring prolonged therapy [151, 152].”
Mansouri, M., Mansouri, K., Taheri, Z., Alhashemi, S. H., & Dehshahri, A. (2025) · BioDrugs · doi:10.1007/s40259-025-00711-7 · Cited by 10
Toxicologic Neuropathology of Novel Biotherapeutics
Bangari, D. S., Lanigan, L. G., Cramer, S. D., Grieves, J. L., Meisner, R., Rogers, A. B., Galbreath, E. J., & Bolon, B. N. (2023) · Toxicologic Pathology · doi:10.1177/01926233241230542 · Cited by 7
“32 Multiplex labeling may facilitate dual localization of the test article and its engagement with target in a cell-specific manner.”
BackgroundSelf-citationBelgrad, J., Summers, A., Landles, C., Greene, J. R., Hildebrand, S. R., Knox, E. G., Sapp, E., Yamada, N., Furgal, R. C., Miller, R., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.06.24.661398 · Cited by 7
“Additional clinically advanced modalities including ASOs 53 , lipophilic conjugated siRNA (C16), 56 and transferrin receptor-coupled oligonucleotides that can cross the blood-brain-barrier 57 can also be programmed to silence MSH3 alone or in combination with HTT .”
Sorets, A. G., Schwensen, K. R., Francini, N., Kjar, A., Abdulrahman, A. M., Shostak, A., Katdare, K. A., Schoch, K. M., Cowell, R. P., Park, J. C., et al. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf600 · Cited by 6
“For example, unconjugated siRNA structures administered carrier-free into CSF penetrate throughout the CNS but are not sufficiently internalized by cells to achieve potent gene silencing [ 8 ].”
Amphiphilic Oligonucleotide Derivatives—Promising Tools for Therapeutics
Bauer, I., & Dmitrienko, E. V. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16111447 · Cited by 6
“Nevertheless, cholesterol-conjugated ONs remains limited to liver The results of active studies of unbranched fa tt y acids have demonstrated that they may serve as a promising vehicle for the delivery of tON to muscle tissue [121–123]. cells and, to a lesser cells [108].”
Modulation of TTR gene expression in the eye using modified siRNAs
Hu, J., Gong, X., Kundu, J., Datta, D., Egli, M., Manoharan, M., Mootha, V. V., & Corey, D. R. (2025) · Nucleic Acids Research · doi:10.1093/nar/gkaf409 · Cited by 7
“Recently, lipid modification has been described as a general approach to delivery to extra-hepatic tissues, including CNS, lung, and eye [ 9 ].”
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Programmable Single-Stranded Circular Antisense Oligonucleotides for Multitarget Gene Therapy
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Self-citationCholesterol-Modified Anti-Il6 siRNA Reduces the Severity of Acute Lung Injury in Mice
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“Currently, the clinical use of siRNA is limited to liver diseases; however, methods for delivering RNA to other organs, including the brain and spinal cord [3,4], kidneys [5,6], spleen [7], and lungs [3,8], are currently under development.”
BackgroundHarnessing nucleic acid technologies for human health on earth and in space
Sarli, S. L., & Watts, J. K. (2022) · Life Sciences in Space Research · doi:10.1016/j.lssr.2022.08.006 · Cited by 6
“…of macromolecules (sugars, amino acids, lipids, and even other nucleic acids) has emerged as a promising strategy to promote tissue or cell-type selective oligonucleotide trafficking and uptake (Song et al. 2005, McNamara et al. 2006, Biscans et al. 2019, Ostergaard et al. 2019, Brown et al. 2022).”
Liu, D., Yu, H., Liu, Z., Wang, L., Liu, D., & Cao, X. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103832 · Cited by 5
Non-cationic carriers for siRNA delivery: Current progress and potential applications
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Functional bioconjugates for precision delivery of nucleic acid therapeutics
Sharma, H., Kumar, V., & Bahal, R. (2025) · Trends in Chemistry · doi:10.1016/j.trechm.2025.10.002 · Cited by 6
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“While its size is relatively modest compared to the overall siRNA molecule, Brown et al. (2022) [72] undertook a thorough investigation of the potential effects of C16 incorporation and determined the optimal positioning for its integration, as detailed below.”
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Oxytocin lipidation expanding therapeutics for long-term reversal of autistic behaviors in rats
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Non‐Viral RNA Delivery During Pregnancy: Opportunities and Challenges
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Beyond cytotoxic potency: disposition features required to design ADC payload
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“Specifically, these molecules because of their size and high negative charge are precluded from passive uptake of into cells (Brown et al. 2022) and secondarily unmodified siRNAs typically are associated with short half-life under physiological conditions due to rapid degradation by extracellular…”
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TAMing Gliomas: Unraveling the Roles of Iba1 and CD163 in Glioblastoma
Fuse, H., Zheng, Y., Alzoubi, I., & Graeber, M. B. (2025) · Cancers · doi:10.3390/cancers17091457 · Cited by 7
“However, the method for delivering siRNA into CNS parenchyma poses a substantial challenge, and the efficacy is low even when siRNA is delivered directly into the cerebrospinal fluid (CSF) [105].”
Chemical Insights into Oligonucleotide–Protein Binding for Therapeutic Applications
Gupta, S., Gupta, A., Mukherjee, M., Bose, S., & Sinha, S. (2025) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5c00427 · Cited by 6
Multimeric Conjugates Using Engineered Peptide Scaffolds for Efficient siRNA Delivery
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Cleavable Hydrophobic Anchors Optimize Immunomodulatory Effects of Oligonucleotides
Luo, T., Kim, Y. J., Cushing, A., Ma, Y., Han, Z., Johnson, R. E., Pascall, M. J. P., & Mirkin, C. A. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c15110 · Cited by 4
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The Versatile Applications of Antisense Oligonucleotides in Modern Medicine
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“More recently, systematic optimization has generated lipid-conjugated siRNA and ASO platforms designed for delivery to extrahepatic tissues, including CNS and peripheral neurons [126,128,129].”
Therapeutic oligonucleotides revisited: Focus on siRNA and antisense technologies
Chen, L., Xu, J., Li, J., Liu, G., & Ma, H. (2026) · The Innovation Drug Discovery · doi:10.59717/j.xinn-drugdisc.2026.100007 · Cited by 6
Self-citationNear Sequence Homology Does Not Guarantee siRNA Cross-Species Efficacy
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Recent advances and clinical prospects of non-viral brain-targeted gene delivery systems
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Effective carrier-free gene-silencing activity of sphingosine-modified siRNAs
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The RNA delivery dilemma—lipid versus polymer nanoparticle platforms
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“Notably, Alnylam Pharmaceuticals' ongoing phase II clinical trials for an intrathecal siRNA lipid-based therapy targeting Alzhei-mer’s-related tauopathies have shown that nucleic acids can reach the brain via cerebrospinal fluid after regional injection (NCT05231785, NCT06393712) [157].”
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An acyclic nucleic acid-modified siRNA targeting CAG expansions for polyglutamine disease treatment
Maeda, K., Hirunagi, T., Sahashi, K., et al. (2025) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2025.102802 · Cited by 3
“Additional incorporation of phosphorothioate linkages, vinylphosphonate, or lipophilic chain conjugates or conversion to a divalent siRNA 52–55 may enhance the pharmacokinetic and pharmacodynamic properties of S9-SNA.”
Yanagidaira, M., Nagata, T., Hasegawa, J., Ishii, T., Ebihara, S., Nawa, M., & Yokota, T. (2025) · Nature Communications · doi:10.1038/s41467-025-66765-x · Cited by 3
“Previous studies of siRNA or ASO administered via IT injection reported that activity in the striatum, which lies upstream of the CSF fl ow, tended to be lower than that in other regions, such as the brainstem 4,34 .”
Fakih, H. H., Abideen, M. Z. U., Rachid, M. O., Gross, K. Y., Ormsby, T. J. R., Ross, V. M., Gagnon, R., Dahlke, C. D., Furgal, R. C., Lochmann, C., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-68993-1 · Cited by 5
“To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/”
InfluentialBravo‐Hernández, M., Mazur, C., Chen, H., Fradkin, L., Searcy, J., Burel, S. A., Kelly, M., Bruening, D., O’Rourke, J. G., Cai, Y., et al. (2026) · Nucleic Acids Research · doi:10.1093/nar/gkag057 · Cited by 9
“To further assess this effect, we tested an additional siRNA (siRNA B, previously optimized for IT delivery in rats, but was not evaluated for tolerability [ 36 ]) and a different ASO sequence (ASO B, maintaining the same chemistry).”
Advances in RNA delivery to extrahepatic tissues and cells
Li, Z., Guo, S., & Huang, Y. (2026) · Journal of Controlled Release · doi:10.1016/j.jconrel.2026.115170 · Cited by 4
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Oligonucleotide therapeutics for neurodegenerative diseases
Li, V. C., & Huang, Y. (2024) · NeuroImmune Pharmacology and Therapeutics · doi:10.1515/nipt-2024-0013 · Cited by 3
“This intracerebroventricular delivery of siRNA has been evaluated in a preclinical mouse model of Alzheimer’s disease, which showed that this amyloid precursor protein-targeting siRNA improved behavioral and physiological abnormalities [5].”
InfluentialA dual-locked cyclopeptide–siRNA conjugate for tumor-specific gene silencing
Li, C., Sun, S., Kong, H., Xie, X., Liang, G., Zhang, Y., Wang, H., & Li, J. (2024) · RSC Chemical Biology · doi:10.1039/d4cb00247d · Cited by 3
Self-citationRare coding variants in CHRNB2 reduce the likelihood of smokingPreprint
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Preclinical development of siRNA conjugates to target tumor antigens
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“…been reported that head groups such as phosphatidylcholine may affect the tissue distribution of lipophilic-siRNAs [14]. siRNA conjugated with palmitic acid at the central position (2’-O-C16-siRNA) has shown significant, prolonged RNAi effects in the central nervous system, eyes, and lungs [15].”
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Platform Assessment of Concentration–QTc Relationship Across GalNAc–siRNA Molecules
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“Nearly two decades of work on siRNA design, delivery solutions, and chemical optimization has allowed the use of siRNAs to target liver as well as extrahepatic tissues such as central nervous system (CNS), eye, and lung [2–4].”
Technology for Nucleic Acid Delivery in the Treatment of Hematological Malignancies
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Toward nanomedicine-enabled RNA therapeutics for Alzheimer’s disease
Kara, G., & Villapol, S. (2026) · Molecular Neurodegeneration Advances · doi:10.1186/s44477-026-00026-z · Cited by 4
“It employs Alnylam’s proprietary C16-siRNA conjugate technology, in which a 2 ′ -O-hexa- decyl lipid is attached to siRNA, enhancing CNS distribution following intrathecal administration [224, 225].”
Li, L., Harp, J. M., Chaput, J. C., et al. (2024) · Current Protocols · doi:10.1002/cpz1.1088 · Cited by 2
“O -hexadecyl conjugation at position 16 of the sense strand was shown to result in potent and durable silencing in the central nervous system (CNS) (Brown et al., 2022).”
BackgroundSelf-citation“Current and emerging drug therapies in Alzheimer’s disease: A pathophysiological Perspective”
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Complexes and Supramolecular Associates of Dodecyl-Containing Oligonucleotides with Serum Albumin
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Complexes and supramolecular associates of dodecyl-containing oligonucleotides with serum albumin
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Self-delivering CRISPR RNAs for AAV Co-delivery and Genome Editing in vivoPreprint
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“Importantly, our study also shows that knowledge acquired from the rapidly evolving oligonucleotide therapeutic fields (16, 17, 57, 65, 87) can be readily applied to improve the distribution and efficiency of self-delivering crRNA in vivo.”
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Application of small interfering RNA technology in cytochrome P450 gene modulation
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Research progress of antibody coupling technique in targeted drug delivery
Li, M., Wang, T., Tan, D., Wang, M., Lei, C., Wang, Y., & Hu, S. (2025) · Interdisciplinary medicine · doi:10.1002/inmd.20240108 · Cited by 1
Model-Assisted Process Optimization for Trivalent Ligand-siRNA Conjugation via CuAAC Click Chemistry
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“(Brown et al., 2022).”
Self-citationNucleic acid drug delivery in ophthalmology: Emerging trends and future perspectives
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Chen, K., Wang, J., Liu, Q., et al. (2026) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2026.125123 · Cited by 1
Getting the message: low-plex detection of RNA in tissues
Spencer‐Dene, B., & Miranda, E. (2026) · Frontiers in RNA Research · doi:10.3389/frnar.2026.1749833 · Cited by 1
“…unlabelled single stranded ASOs in FFPE and frozen tissue sections by IHC (Kordasiewicz et al., 2012; Hung et al., 2013) and immunofluorescence (Brown et al., 2022; Ly et al., 2025), but unlike the miRNAscope and RNAscope Plus smRNA-RNA ISH assays shown in Table 1, are not specific for…”
Metadata
- Authors
- Brown, K. M., Nair, J. K., Janas, M. M., Anglero-Rodriguez, Y. I., Dang, L. T. H., Peng, H., Theile, C. S., Castellanos-Rizaldos, E., Brown, C., Foster, D., Kurz, J., Allen, J., Maganti, R., Li, J., Matsuda, S., Stricos, M., Chickering, T., Jung, M., Wassarman, K., Rollins, J., Woods, L., Kelin, A., Guenther, D. C., Mobley, M. W., Petrulis, J., McDougall, R., Racie, T., Bombardier, J., Cha, D., Agarwal, S., Johnson, L., Jiang, Y., Lentini, S., Gilbert, J., Nguyen, T., Chigas, S., LeBlanc, S., Poreci, U., Kasper, A., Rogers, A. B., Chong, S., Davis, W., Sutherland, J. E., Castoreno, A., Milstein, S., Schlegel, M. K., Zlatev, I., Charisse, K., Keating, M., Manoharan, M., Fitzgerald, K., Wu, J.-T., Maier, M. A., & Jadhav, V.
- Affiliations
- Alnylam Pharmaceuticals (United States) (US)
- Corresponding author
- Maier, Martin A.
- Jadhav, Vasant
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2022-06-02
- Volume
- 40
- Issue
- 10
- Pages
- 1500-1508
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- OpenAlex
- W4281688566
- Cited by
- 258
- References
- 55
- Citations by year
- 2026: 56 · 2025: 62 · 2024: 68 · 2023: 56 · 2022: 16
- FWCI
- 13.94
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Biotechnology (publishedVersion)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Funded by Alnylam Pharmaceuticals, Cambridge, MA USA
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- siRNA therapeutics, intrathecal drug delivery, intracerebroventricular administration, intravitreal delivery, amyloid precursor protein, Alzheimer's disease, non-human primates
- MeSH terms
- RNAi Therapeutics, Animals, Primates, Amyloid beta-Protein Precursor, RNA Interference, RNA, Small Interfering, Mice
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