Brigham and Women's Hospital has received USD 1.47 million in first-year funding from the National Institute on Aging to test whether the antiviral lamivudine (3TC) can target retrotransposon activity and Alzheimer's disease pathology in adults with Down syndrome (DS).
The award funds a seamless Phase Ib/Phase IIa program led by contact principal investigator Shalender Bhasin alongside principal investigators Brian Kalish and Brian G. Skotko. The Phase Ib component will assess safety, tolerability, and pharmacokinetics of multiple ascending doses of lamivudine in adults with DS over four weeks, with target engagement evaluated by measuring reverse transcriptase activity and intracellular lamivudine triphosphate in peripheral blood mononuclear cells (PBMCs). If pre-specified go/no-go criteria are met, the program transitions to a six-month, randomized, placebo-controlled, double-blind Phase IIa trial measuring changes in plasma and cerebrospinal fluid Alzheimer's disease biomarkers including pTau-217, total tau, neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), amyloid beta-42 (Aβ42), and Aβ40, alongside type-I interferon-stimulated gene expression and exploratory neuropsychological outcomes. The USD 1.47 million award covers the first budget year of the two-year program, with progression from the UG3 Phase Ib component to the UH3 Phase IIa study contingent on prespecified milestones.
The scientific rationale centers on retrotransposons — ancient mobile genomic sequences whose aberrant reactivation the investigators hypothesize contributes to Alzheimer's disease pathogenesis in DS. The researchers propose that altered chromatin regulation in DS increases transposable element (TE) expression, while tau can further activate TEs, generating nucleic acid intermediates capable of triggering innate immune signaling and neuroinflammation.
Lamivudine, an FDA-approved nucleoside reverse transcriptase inhibitor used in HIV-1 and hepatitis B virus treatment, blocks the retrotransposition cycle and prevents cytoplasmic DNA intermediate formation. The investigators report TE overexpression in post-mortem human DS brain tissue, and cite preclinical Alzheimer's disease model data showing lamivudine attenuated neuroinflammation, reduced tau phosphorylation, and improved cognitive performance, as well as a pilot study in neurotypical individuals with Alzheimer's disease and supportive epidemiological data.