Comparative route of administration studies using therapeutic siRNAs show widespread gene modulation in Dorset sheep

Abstract

BMDCG, and CMF hold patents and/or patent applications (WO2016161374A1 and US10478503B2) on the use of divalent siRNAs and disease-specific siRNA sequences.

Biodistribution and delivery of oligonucleotide therapeutics to the central nervous system: Advances, challenges, and future perspectives

“…(2022) found that conjugation of 2′‐O‐hexadecyl (C16) and 5′‐(E)‐vinylphosphonate to siRNA provided wider biodistribution and higher siRNA concentration after IT administration in rats and NHPs, producing a more potent therapeutic effect than nonconjugated siRNA did. In other studies (Ferguson et al., 2021; Jafar‐Nejad et al., 2021), C16‐conjugated siRNA concentrations were also lower in the striatum in the deep brain than in other regions, and mRNA knockdown tended to be weaker in the striatum. As with the di‐siRNA case described above, the molecular weight and physicochemical properties of OTs may impact their brain distribution.…”

“…In sheep receiving a 50‐mg dose of di‐siRNA, an extremely high concentration (100 μg/g tissue) of di‐siRNA was detected in the brain (Ferguson et al., 2021); this value was much higher than the brain di‐siRNA concentration in NHPs receiving a a 25‐mg dosage (approximately 10 μg/g tissue) (Alterman et al., 2019). The prolonged CSF retention attributable to the large molecular weight and charge may contribute to this high concentration.…”

“…Following IT and ICV administration of di‐siRNA to a larger animal (sheep), low distribution to the deep brain was observed via both ROAs (Ferguson et al., 2021). Contrarily, uniform distribution of ASOs in the brain and knockdown of target genes was observed in mice receiving ICV administration (Jafar‐Nejad et al., 2021).…”

Di-valent siRNA Mediated Silencing of MSH3 Blocks Somatic Repeat Expansion in Mouse Models of Huntington’s Disease

“…Additionally, the pharmacokinetics and pharmacodynamics (PK/PD) of Di-siRNA makes it a safe and effective drug modality for MSH3 modulation, where majority of the injected dose is retained in the CNS. Di-valent siRNAs, when administered by CSF infusion, achieve 30-40% retention of the injected dose in the CNS ( 31 ) ( 57 ), where it broadly distributes ( 30 ) –to brain structures highly affected in HD –and can silence a gene target for up to six months. Importantly, di-valent siRNAs show limited accumulation in liver and kidney and no detectable presence in the colon, a tissue in which MSH3 silencing is associated with cancer ( 58, 59 ).…”

“…By slowing clearance from cerebrospinal fluid and enhancing uptake into cells (29), di-valent siRNA support broad distribution and potent modulation of target gene expression in mouse and non-human primate (NHP) brain for up to six months after a single injection (30). The placement of cerebrospinal fluid (CSF) infusion (intrathecal or intracerebroventricular) has no significant impact on di-valent siRNA distribution in the large brains, confirming clinical translatability (31). di-valent siRNA could allow for therapeutic modulation of MSH3 expression in CNS, so long as a potent, fully modified siRNA sequence targeting MSH3 can be identified (30).…”