Lamivudine as a Novel Clinical Effort for Rett Syndrome

Rett syndrome (RTT) is a rare genetic neurodevelopmental disorder caused primarily by loss-of-function mutations in the MECP2 gene, leading to progressive impairments in motor, cognitive, and communicative function after an initial period of apparently typical development. Currently, there are no medications that change the course of the disease, and treatment is mainly focused on managing symptoms. Functional MeCP2 represses the activity of the LINE-1 (L1) retroelement, and loss of this repression may result in increased L1 accumulation in glial cells in the brain, promoting genomic instability, oxidative stress, and neuroinflammation associated with RTT pathophysiology. Lamivudine inhibits L1 reverse transcription and has shown beneficial effects in preclinical neuronal culture and MeCP2-deficient mouse models, including reduced inflammatory and oxidative stress markers, improved neurological and behavioral outcomes, and increased survival. In this study, each participant is evaluated before and after receiving treatment, allowing changes to be assessed within the same individual over time. Following screening and baseline?baseline Measurements taken at the start of the study, before any study treatment, so that later results can be compared with them. assessments, participants enter a treatment phase during which oral lamivudine is administered for a defined period. Longitudinal clinical, laboratory, and safety evaluations are conducted at scheduled visits, followed by a post-treatment follow-up?follow-up The period after treatment or enrolment during which participants are observed or contacted, for example to record side effects or outcomes. period to assess the persistence of effects. A 24-week intervention period was selected as a feasible and acceptable duration for participants and caregivers and as an appropriate timeframe?timeframe The period over which an outcome is measured, for example 'at 12 weeks'. It is not necessarily the total length of the study. for an initial open-label?open-label No masking is used, so the assigned intervention is not deliberately hidden from participants or study staff. evaluation of therapeutic potential. This duration is expected to provide sufficient exposure to lamivudine to allow detection of short-term clinical and biological changes suggested by preclinical studies, while also enabling systematic assessment of safety and tolerability in this population. Participants may continue their usual medical treatments, including medications for seizures and other supportive therapies, as long as these treatments remain stable during the study, unless a change is medically necessary. Caregivers receive standardized instructions on medication administration, and adherence is monitored throughout the treatment phase through caregiver reporting and visit-based verification to ensure accurate assessment of treatment exposure. Clinical assessments employ validated clinician and caregiver-reported instruments to evaluate symptom severity, functional status, quality of life, and seizure activity, capturing changes across motor, behavioral, and daily functioning domains relevant to RTT. Safety is monitored continuously through adverse event?adverse event Any unwanted medical problem that happens during a study, whether or not it was caused by the treatment. A 'serious' adverse event is one that meets specific criteria, such as causing death, being life-threatening, requiring or prolonging hospital admission, causing significant disability, or another medically important outcome. surveillance, routine clinical evaluations, and laboratory testing, with predefined criteria for treatment interruption if clinically indicated. Venous blood samples are collected at baseline and during treatment to evaluate systemic biomarkers related to oxidative stress, inflammation, and neurodevelopment. These measures complement clinical outcomes and explore potential mechanistic effects of lamivudine treatment. In addition to the biomarkers reported as outcome measures?outcome measures Something the study measures to judge its results, such as a symptom score, a blood test or survival. Outcomes are grouped as primary, secondary and sometimes exploratory., a panel of exploratory, hypothesis-generating biomarkers will be analyzed, including markers of oxidative stress, neuroinflammation and neurodevelopment, mitochondrial and energy metabolism, and nutritional and micronutrient status. These analyses are not considered clinical endpoints and are not reported as outcome measures. As a translational research component, skin punch biopsies from a subset of participants are used to establish a dermal fibroblast biobank?biobank A collection of biological samples, such as blood or tissue, stored with medical information so that researchers can study them later., enabling the generation of patient-derived induced pluripotent stem cells and brain organoids. These models will be used in exploratory laboratory studies to investigate cellular and molecular mechanisms in RTT and responses to lamivudine, without being considered clinical endpoints. Based on preclinical evidence and the proposed mechanism of action, lamivudine treatment is expected to be safe and well-tolerated in individuals with Rett syndrome. Clinically, it may lead to improvements in motor function, social engagement, and overall symptom severity, while reducing seizure frequency and enhancing quality of life. Biologically, lamivudine is anticipated to modulate oxidative stress and inflammatory pathways, potentially restoring a more balanced neurodevelopmental environment. The combined clinical and laboratory observations from this study will provide critical insights into the therapeutic potential of lamivudine and inform future research directions in RTT.