Repurposing a reverse transcriptase inhibitor to target retrotransposons and prevent alzheimer's disease in people with down syndrome: a two-phase UG3/UH3 clinical drug development program

The National Institute on Aging awarded Brigham & Women's Hospital Inc. a cooperative agreement totaling $1,478,201 on August 15, 2026, under the Aging Research program (CFDA 93.866) to conduct a two-phase clinical drug development program evaluating lamivudine (3TC), a reverse transcriptase inhibitor, as a potential treatment to prevent and slow Alzheimer's disease in people with Down syndrome.

The research addresses evidence that aberrant activation of retrotransposons—transposable elements in the human genome—drives Alzheimer's disease pathogenesis, particularly in individuals with Down syndrome who develop AD neuropathology and dementia at substantially younger ages than the general population. Preclinical models demonstrate that lamivudine blocks the retrotransposition cycle, attenuates neuroinflammation, decreases tau phosphorylation, and improves cognitive performance. The UG3 phase includes a Phase 1B study to determine safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses, integrated with a Phase 2A proof-of-concept trial for early-stage evaluation of 3TC to prevent and treat AD in people with Down syndrome.

Performance of work is located in Boston, Massachusetts. The period of performance extends from the award date through July 31, 2028. Brigham & Women's Hospital Inc., doing business as Department of Faulkner Pathology, is a subsidiary of Partners Healthcare System Incorporated and serves as the prime recipient. The hospital operates as a coordinating center and research site across multiple NIH-funded clinical trials and multicenter consortia.

Abstract

Nearly all individuals with down syndrome (DS) will develop alzheimer's disease (ad) neuropathology and ad- related dementia at a substantially younger age than people without DS. The prevention and treatment of ad and the associated dementia are high priorities for people with DS and their families. Recent evidence suggests that aberrant activation of ancient viral sequences in the human genome- transposable elements (TE) including retrotransposons-is a critical component of ad pathogenesis. Disruptions in chromatin structure and gene expression in DS unleash TE expression. Further, TAU activates TE to generate double- stranded RNA and trigger innate immune responses, neuroinflammation, and neurodegeneration. Our data confirm profound TE over-expression in the human brain of people with DS (preliminary studies). Lamivudine (3TC) is a nucleoside reverse transcriptase inhibitor used in the treatment of HIV-1 and HBV infections that blocks the retrotransposition cycle of TES, preventing the formation of cytoplasmic DNA intermediates. In preclinical models of ad, 3TC attenuated neuroinflammation, decreased TAU phosphorylation, and improved cognitive performance. Promising data from preclinical models, a pilot study in neurotypical people with ad, and epidemiologic studies lead US to hypothesize that 3TC may be a potential treatment to attenuate the expression of TES, prevent neuroinflammation, and slow neurodegeneration in individuals with DS. In conformity with the nofo, we propose a seamless plan to integrate a phase 1B trial with a phase 2A proof- of-concept trial for early-stage evaluation of 3TC TP prevent and treat ad in people with DS. The UG3 phase will include a phase 1B study (aim 1) to determine the safety, tolerability, PK, and PD of multiple ascending doses of 3TC daily for 4 weeks in adults with DS. Safety will be assessed using structured monitoring of adverse events and safety laboratory tests. PK parameters (caverage 0-24H, cmax, tmax, z, auclast, AUC24HR, and T1/2) will be computed using nonparametric methods. Target engagement (PD) will be assessed by measuring reverse transcriptase activity and intracellular 3TC triphosphate in peripheral blood mononuclear cells (pbmcs). If pre-specified go-no-go criteria are met, the UH3 phase will include a phase 2A, proof-of-concept, 6-month randomized, placebo-controlled, double-blind, parallel group study of 3TC in adults with DS (aim 2). In addition to safety evaluation, we will measure changes from baseline to week 24 in: (1) ad biomarkers, including ptau-217, total TAU, NFL, gfap, AΒ42, and AΒ40 in plasma and CSF; (2) type-i IFN-stimulated genes in pbmcs and plasma inflammation markers; and (3) exploratory clinical neuropsychological outcomes. The proposed application of 3TC for treating ad is innovative because IT repurposes an FDA-approved medication to target a new mechanism of ad in people with DS. The proposed phase 1B and phase 2A trials, with attributes of rigorous trial design and strengths of an outstanding interdisciplinary team and infrastructure, offer an extraordinary opportunity to rigorously evaluate this promising drug.