A Phase I, Randomized, Double-Blind, Placebo-Controlled Trial of Intracisternal Engineered Autologous Exosomes (NV-101) to Restore Neuronal Proteostasis in Early Alzheimer's Disease: The RESTORE Protocol

BackgroundThe current therapeutic landscape for Alzheimers disease (AD) offers limited efficacy. The failure of the neuronal proteostasis network a system critical for preventing toxic protein aggregation is a fundamental pathological process in AD. Molecular chaperones, which are deficient in the AD brain, represent a compelling therapeutic target. A major obstacle has been delivering large biologics like chaperones across the blood-brain barrier. Engineered exosomes offer a promising platform for neuron-specific delivery of nucleic acid cargo. ObjectiveThe primary objective is to evaluate the safety and tolerability of a single intracisternal dose of NV-101, an autologous dendritic cell-derived exosome engineered with neuron-targeting peptides and DNAJB6 mRNA, compared to placebo in participants with early AD. Secondary objectives are to assess its biological activity through cerebrospinal fluid (CSF) biomarkers. MethodsThe RESTORE trial is a single-center, randomized, double-blind, placebo-controlled, dose-escalation study. Eighteen participants with biomarker-confirmed early AD will be enrolled across three sequential dose cohorts (Low, Medium, High). Participants will be randomized in a 2:1 ratio to receive either NV-101 or placebo (excipient buffer) via a single intracisternal magna injection. The primary outcome is the incidence of treatment-emergent adverse events over 52 weeks. Secondary outcomes include change from baseline in CSF levels of DNAJB6 protein, oligomeric amyloid-{beta}42, and phosphorylated tau (p-tau181). Exploratory outcomes include neuroimaging and cognitive measures. ConclusionsThis first-in-human study will generate critical safety and initial proof-of-mechanism data for a novel therapeutic strategy aimed at correcting proteostatic failure in AD.