J001 Preliminary results from the first-in-human study of ER2001, an innovative treatment for Huntington’s disease using in vivo self-assembled sirna

<h3>Background</h3> ER2001 is a genetic circuit (plasmid) encoding both a neuron-targeting rabies virus glycoprotein (RVG) tag and an HTT siRNA. This circuit is able to reprogram liver cells to transcribe and self-assemble HTT siRNA into RVG-tagged exosomes after intravenous administration. The RVG guided HTT siRNA is further delivered through the exosome-circulating system to the cortex and striatum. In the preclinical studies ER2001 lowered mHTT, improved behavioural deficits and ameliorated neuropathologies <h3>Objective</h3> To evaluate the safety and tolerability of ER2001 in patients with early manifest HD including the pharmacokinetics (PK) of ER2001 in plasma and the exposure of ER2001 in cerebrospinal fluid (CSF). <h3>Methods</h3> This open label, single center pilot study evaluates a single dose of ER2001 followed by multiple doses in eligible patients with early manifest HD. A modified 3 plus 3 dose-escalation design is employed with escalating rules set according to the incidence of dose-limiting toxicity (DLT) including assessment of safety, PK, PD and UHDRS. Participants will receive totally 8 intravenous injections of ER2001 and the treatment period of 14 weeks will be followed by an observation phase of 84 days after the last injection. The Biomarkers will be measured to examine the target engagement. <h3>Results</h3> We have enrolled 6 patients and revealed a total of 9 mild-moderate AEs in 2 female patients. None of AEs is related to ER2001. No SAE is present. Lab test indicated that ER2001 could lower CSF NfL level. <h3>Conclusions</h3> The safety review committee (SRC) with accesses to all unblinded data thoroughly reviewed the safety data and concluded that to date no safety signals of concern emerged. (Safety, PK, PD, and clinical outcomes will be updated once available) (ClinicalTrials.gov Identifier: NCT 06024265)