Cellular immune changes during severe antisense oligonucleotide-associated thrombocytopenia in a nonhuman primate model.

Antisense oligonucleotides (ASOs) are a new class of single-stranded DNA-based drugs that hold great therapeutic potential. A low incidence of severe, dose-dependent, and reversible thrombocytopenia (TCP) (platelets < 50 K/μl) has been reported in nonhuman primate (NHP) populations, following treatment of monkeys with 2'-O-methoxy ethyl ASOs (2% to 4% at doses > 8 to 10 mg/kg/week). The potential mechanisms for this effect were studied using the Mauritian-sourced NHPs, which were shown to be more susceptible to ASO-induced TCP than Asian-sourced animals.

Complement C3d/C4d Deposition on Platelets Correlates with 2'-O-Methoxyethyl Antisense Oligonucleotide-Induced Thrombocytopenia in Monkeys.

2'-O-Methoxyethyl antisense oligonucleotide (2'-MOE ASO)-induced severe thrombocytopenia (TCP) [platelet (PLT) count <50 K/μL] was observed in the Asian-sourced cynomolgus monkeys with low incidence (2%-4% at doses >5 mg/kg/week). The potential mechanisms for TCP were studied using the Mauritian-sourced cynomolgus monkeys, which were shown to be more susceptible to ASO-induced TCP, along with the Asian-sourced animals. ISIS 405879, a 2'-MOE ASO, induced severe TCP (PLT <50 K/μL) in seven of nine Mauritian-sourced monkeys but not in the Asian-sourced monkeys after 16 weeks of treatment at 40 mg/kg/week.

Sequence-specific 2'-O-methoxyethyl antisense oligonucleotides activate human platelets through glycoprotein VI, triggering formation of platelet-leukocyte aggregates.

Antisense oligonucleotides (ASO) are DNA-based, disease-modifying drugs. Clinical trials with 2'-O-methoxyethyl (2'MOE) ASO have shown dose- and sequence-specific lowering of platelet counts according to two phenotypes. Phenotype 1 is a moderate (but not clinically severe) drop in platelet count.

The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration.

Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells.

Underlying Immune Disorder May Predispose Some Transthyretin Amyloidosis Subjects to Inotersen-Mediated Thrombocytopenia.

Inotersen, a 2'-O-methoxyethyl (2'-MOE) phosphorothioate antisense oligonucleotide, reduced disease progression and improved quality of life in patients with hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) in the NEURO-TTR and NEURO-TTR open-label extension (OLE) trials. However, 300 mg/week inotersen treatment was associated with platelet count reductions in several patients. Mean platelet counts in patients in the NEURO-TTR-inotersen group remained ≥140 × 10/L in 50% and ≥100 × 10/L in 80% of the subjects.

Investigation into the Mechanism(s) That Leads to Platelet Decreases in Cynomolgus Monkeys During Administration of ISIS 104838, a 2'-MOE-Modified Antisense Oligonucleotide.

ISIS 104838, a 2'-O-methoxyethyl (2'-MOE)-modified antisense oligonucleotide (ASO), causes a moderate, reproducible, dose-dependent, but selflimiting decrease in platelet (PLT) counts in monkeys and humans. To determine the etiology of PLT decrease in cynomolgus monkeys, a 12-week repeat dose toxicology study in 5 cynomolgus monkeys given subcutaneous injections of ISIS 104838 (30-60 mg/kg/week). Monkeys were also injected intravenously with 111Indium(In)-oxine-labeled PLTs to investigate PLT sequestration.

Assessment of the Effects of 2'-Methoxyethyl Antisense Oligonucleotides on Platelet Count in Cynomolgus Nonhuman Primates.

Decreases in platelet (PLT) counts observed in nonhuman primates (NHPs) given 2'-O-methoxyethyl modified antisense inhibitors (2'-MOE ASOs) have been reported, but the incidence and severity of the change vary considerably between sequences, studies, and animals. This article will broadly illustrate the spectrum of effects on PLT count in NHPs. From queries of an NHP safety database representing over 102 independent 2'-MOE ASOs, from 61 studies and >2200 NHPs, two patterns of PLT changes emerged.