Clinical Trials 

Targeting GRIN-Related Neurodevelopmental Disorders Clinical Trial**

The study uses a randomized, doubleblind, placebocontrolled crossover design, meaning that participants will receive both Lserine and placebo at different times, allowing each individual to serve as their own comparison. Participation includes a screening visit, a short baseline observation period, and regular outpatient followup visits over a minimum period of one year.

Throughout the study, participants undergo noninvasive clinical, developmental and neurological assessments, with careful safety monitoring. To ensure participant safety, only individuals with proven lossoffunction variants are eligible, reflecting current evidence that Lserine may be harmful in gainoffunction GRIN variants.

The study aims to improve understanding of targeted treatments for GRINrelated disorders while prioritizing safety, scientific rigor and the wellbeing of participating families.

Families interested in taking part in this international clinical study are invited to contact the study coordinator at each site. 

In Italy:

Dr. Simona Balestrini (Meyer Hospital Florence). Contact Giulio Peroni’s email: giulio.peroni@meyer.it

In France:

Dr. Eleni Panagiotakaki (Hospices Civils de Lyon). Contact Lea Barbieri’s email: lea.barbieri01@chu-lyon.fr

In Poland: 

Dr. Sergiusz Józwiak (Children’s Memorial Health Institute in Warsaw). Contact Magdalena Mlostek’s email: magdalena.mlostek@ipczd.pl

Who Can Participate? (Key Inclusion Criteria)

Participants must:

• Be between 2 and 30 years old.
• Have a clinical diagnosis of a GRIN-related neurodevelopmental disorder (with epilepsy and/or intellectual disability and/or behavioural challenges).
• Carry a pathogenic lossoffunction variant in GRIN1, GRIN2A, GRIN2B, or GRIN2D.
• Provide informed consent (and assent where required).
• Have caregivers able to follow study procedures.

**If currently taking Lserine, a 1week washout period is required before the screening visit.

Study Timeline

The study involves:

1. Screening visit
2. 4week baseline observation period
3. Treatment cycles, each lasting 6 months:
   • 3 months Lserine
   • 3 months placebo
     (order randomized)
4. Study visits every ~3 months, at the end of each treatment block

A minimum of two treatment cycles is required → ~12 months total participation.

All visits are outpatient; no hospital admission or overnight stay is required.

What Assessments Are Included? 

Clinical & Neuropsychological Evaluations

• CGI scales
• VinelandIII or ABAS3
• CBCL / ABCL
• EpiTrack
• Motor assessments
• Sleep questionnaires

Epilepsy-Related Testing

• Seizure diary review
• EEG (for participants with epilepsy)

Additional Procedures

• Transcranial Magnetic Stimulation (TMS) in Italy and France sites
• Blood tests for routine safety labs (small volumes)
• Optional cellular substudy (requires separate consent and negative HBV/HCV/HIV serology)

Functional Evidence Requirement

A lossoffunction (LoF) confirmation is required for enrolment.

If this testing has not been completed, the study team will work with families and collaborators to determine whether functional data exist or can be generated.

Medications During the Study

• No specific antiseizure medications are prohibited.
• Most treatments may continue.
• All medications and supplements — including spermidine — must be:
  • Documented
  • Ideally kept stable throughout the study

Exclusion Criteria

Individuals are not eligible if they:

• Are younger than 2 years
• Have hypersensitivity to study products
• Have unstable medical conditions that pose risk
• Recently participated in another investigational medicinal product trial
• Are pregnant or breastfeeding
• Have GRIN variants without clear LoF evidence (see Functional Evidence Requirement section)

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L-Serine Clinical Trial, at the San Joan de Déu Hospital in Barcelona. CLOSED

Brief summary of the trial:

GRIN-related disorders encompass a new group of inborn Errors of Metabolism according to the recent nosology published by Ferreira et al (Genet Med, 2019).

These rare conditions represent a subtype of paediatric encephalopathies leading to intellectual disability, hypotonia, communication deficits and motor impairment (Orphanet entries: 178469, 289266, 101685, for GRIN1, GRIN2A and GRIN2B, respectively).

Mutations leading to glutamatergic hypotransmission can be potentially treated with L-Serine leading to significant clinical benefits in patients according to a pilot study published by our group (Soto et al, 2019).

In this study, the investigators have included 24 patients  between the ages of 2,6 years and 18 years (average age of 9 years), harbouring GRIN variants functionally anotated as loss-of-function pathogenic variants. Of the 24 patients 6 had a GRIN1 mutation, 5 had a GRIN2A  mutation and 13 had a GRIN2B mutation. The investigators will evaluate dose tolerability, efficacy of the treatment according to neurocognitive and motor scales, as well as the effects of L-serine in microbiome composition.