TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders

GRIN-related neurodevelopmental disorders (GRIN-NDD) are rare genetic conditions caused by pathogenic variants in GRIN1, GRIN2A, GRIN2B, or GRIN2D, which encode subunits of the N-methyl-D-aspartate receptor (NMDAR). NMDARs play a central role in synaptic transmission, plasticity, and neurodevelopment. Variants affecting these genes may result in altered receptor function, most commonly loss of function (LoF), leading to a spectrum of neurodevelopmental phenotypes that include epilepsy, intellectual disability, behavioural abnormalities, sleep disturbances, and motor impairment.

Preclinical and clinical evidence suggests that enhancement of NMDAR co-agonist availability may partially restore receptor function in individuals with LoF GRIN variants. L-serine, a naturally occurring amino acid, serves as a metabolic precursor of D-serine, a major endogenous NMDAR co-agonist. Oral L-serine supplementation has been associated with clinical improvement in small case series and early-phase clinical studies involving individuals with GRIN-NDD due to LoF variants. However, systematic evidence from randomised, blinded studies remains limited, particularly given the rarity and phenotypic heterogeneity of these disorders.

This study is designed to evaluate the clinical effect and safety of L-serine supplementation using an aggregated series of randomised, double-blind, placebo-controlled n-of-1 trials. The n-of-1 approach allows each participant to serve as their own control and is well suited to rare diseases with substantial inter-individual variability. By aggregating data from multiple single-patient trials using Bayesian hierarchical models, the study aims to provide both individual-level and population-level estimates of treatment effect.

Following a baseline observation period, participants will undergo repeated treatment cycles in which L-serine supplementation and placebo are administered in alternating periods. Each cycle consists of two treatment periods of equal duration, with the order of treatments randomised for each cycle. A short washout interval is incorporated at the start of each treatment period to minimise potential carry-over effects. Both participants and investigators remain blinded to treatment allocation throughout the study, except in cases of emergency unblinding for safety reasons.

L-serine and placebo are provided as oral powders for solution and are administered at a fixed weight-based dose divided into three daily administrations. No dose titration is planned. Concomitant treatments, including antiseizure medications and other standard therapies, are permitted and remain stable whenever clinically feasible. Participants are monitored longitudinally through scheduled visits that include clinical evaluations, safety laboratory testing, and protocol-specified assessments.

The primary focus of the study is the assessment of global clinical change associated with L-serine supplementation compared with placebo. Secondary evaluations examine treatment effects across multiple functional domains, including behaviour, cognition, adaptive functioning, motor abilities, sleep quality, and, in participants with epilepsy, seizure frequency and electroencephalographic (EEG) features. These assessments are conducted repeatedly at the end of each treatment period, enabling within-subject comparisons across treatment conditions.

In addition to clinical outcomes, the study incorporates neurophysiological assessments to explore objective biomarkers of treatment response. Transcranial magnetic stimulation (TMS) combined with electromyography (EMG) and electroencephalography (EEG) is used at selected sites to characterise cortical excitability, inhibitory and excitatory balance, and network-level responses to stimulation. These measures are intended to provide mechanistic insights into NMDAR-related cortical function and to identify potential biomarkers that correlate with clinical response to L-serine.

An optional preclinical biomarker substudy is included for a subset of participants who provide additional consent. In this substudy, peripheral blood samples are used to generate induced pluripotent stem cells (iPSCs), which are subsequently differentiated into neuronal cell models and, in selected cases, three-dimensional brain organoids. These patient-derived models are used to examine neuronal development, synaptic function, network activity, and plasticity in vitro, and to assess the effects of L-serine exposure at the cellular and molecular levels. Data from this substudy are exploratory and are intended to support translational interpretation of clinical findings.

Safety monitoring is conducted throughout the study in accordance with Good Clinical Practice principles. Adverse events are systematically collected and evaluated for severity and potential relationship to the study product. Predefined criteria are in place for treatment discontinuation and early withdrawal in the event of clinical worsening or safety concerns. Given the non-pharmacological classification of L-serine as a food for special medical purposes and its prior clinical use, no specific toxicity signals are anticipated; however, ongoing monitoring is implemented to ensure participant safety.

The study is conducted across multiple international centres with expertise in GRIN-NDD. The innovative design of aggregated n-of-1 trials is intended to maximise the interpretability of results in a rare disease context, allowing identification of both average treatment effects and inter-individual variability in response. The findings are expected to inform clinical decision-making, contribute to evidence-based use of L-serine in GRIN-NDD, and support the broader application of n-of-1 trial methodologies in rare neurological disorders.

• Number of adverse events [Срок оценки: From baseline through the end of the last treatment period and the 2-week post-treatment safety follow-up (up to approximately 110 weeks).]
• Change in Clinical Global Impression - Improvement (CGI-I) score [Срок оценки: Assessed at the end of each 3-month treatment period across all completed treatment cycles (minimum 2 cycles, up to 4 cycles; up to approximately 104 weeks)]
• Change in behavioural functioning [Срок оценки: From baseline to the end of each 3-month treatment period across all completed treatment cycles (up to approximately 104 weeks).]
• Change in adaptive functioning [Срок оценки: From baseline to the end of each 3-month treatment period across all completed treatment cycles (up to approximately 104 weeks).]
• Change in cognitive performance [Срок оценки: From baseline to the end of each 3-month treatment period across all completed treatment cycles (up to approximately 104 weeks).]
• Change in motor function [Срок оценки: From baseline to the end of each 3-month treatment period across all completed treatment cycles (up to approximately 104 weeks).]
• Change in sleep quality [Срок оценки: From baseline to the end of each 3-month treatment period across all completed treatment cycles (up to approximately 104 weeks).]
• Change in seizure frequency (epilepsy subgroup) [Срок оценки: From baseline to the end of each 3-month treatment period across all completed treatment cycles (up to approximately 104 weeks).]
• Change in epileptiform discharge frequency on EEG (epilepsy subgroup) [Срок оценки: From baseline to the end of each 3-month treatment period across all completed treatment cycles (up to approximately 104 weeks).]
• Change in neurophysiological biomarkers (TMS-EMG / TMS-EEG) [Срок оценки: From baseline to the end of each 3-month treatment period across all completed treatment cycles (up to approximately 104 weeks).]