Sarepta Therapeutics has registered a first-in-human Phase I trial of SRP-1005 (formerly ARO-HTT), an siRNA conjugate designed to silence the huntingtin gene via subcutaneous injection, in adults with Huntington's disease. The molecule, originally developed by Arrowhead Pharmaceuticals under its TRiM CNS platform and in-licensed by Sarepta in a deal that delivered USD 825 million on closing in early 2025, uses a monovalent anti-transferrin receptor 1 fragment antigen-binding domain to ferry an RNAi payload across the blood-brain barrier without intrathecal delivery — a route that has historically constrained the field and contributed to safety concerns with earlier oligonucleotide programs.
The INSIGHTT study (NCT07536061) is a randomized, double-blind, placebo-controlled, dose-escalation trial enrolling approximately 32 adults across four ascending-dose cohorts at two sites in New Zealand. Participants must carry a genetically confirmed HTT CAG repeat expansion of 40 or more and fall within HD Integrated Staging System Stage 2 or mild Stage 3, restricting enrollment to those with established but not yet advanced disease. The primary endpoint tracks the incidence of treatment-emergent adverse events, serious adverse events, and adverse events of special interest through 24 weeks. Secondary measures characterize drug concentrations in plasma, cerebrospinal fluid, and urine — data that will be central to establishing whether subcutaneous dosing produces meaningful CNS exposure. Primary completion is expected in Q4 2027. The trial is not yet recruiting; the registry record was posted in April 2026.
Huntington's disease is caused by a dominantly inherited CAG trinucleotide expansion in the HTT gene, producing a toxic gain-of-function mutant protein that drives progressive striatal and cortical neurodegeneration. The genetic determinism of the condition has long made it a target for nucleic acid-based silencing strategies, but delivery to the relevant deep brain structures has been the persistent bottleneck. SRP-1005 addresses this through TfR1-mediated transcytosis: the anti-TfR1 fAb binds the transferrin receptor on brain capillary endothelial cells, enabling transport of the attached siRNA across the blood-brain barrier following peripheral dosing. Preclinical data generated at Arrowhead, which informed the November 2024 licensing deal with Sarepta, showed dose-dependent HTT mRNA knockdown in disease-relevant regions including the putamen, caudate, and frontal cortex in non-human primates. The subcutaneous route is intended to avoid the peak-concentration receptor saturation that could limit intravenous dosing while enabling sustained CNS uptake.