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Clinical Trials 

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 haveincluded 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.

L-Serine Clinical Trial:

https://www.clinicaltrials.gov/ct2/show/NCT04646447?term=Serine&cond=GRIN&draw=2&rank=1

The Honeycomb Trial for Radiprodil

Neurvati’s first subsidiary company, GRIN Thereapeutics is developing an investigational product, Radiprodil as a novel therapy for patients diagnosed with GRIN-related disorders. GRIN-related disorders are genetically defined pediatric encephalopathies that present with a spectrum of symptoms, including epilepsy, behavioral disorders, autism, intellectual disability and movement disorders. Radiprodil selectively targets the NR2B (Glun2B protein piece made by the GRIN2B gene) of the NMDA receptors in the brain. Patients affected by a Gain of Function (GoF) mutation in the GluN2B (NR2B) have an overactive neuroreceptor which renders GRIN2B related disorder. By targeting the root cause of the disorder, we believe that Radiprodil has potential to serve as a possible treatment option for these patients. 

The Radiprodil trial is currently aimed at children with a GRIN2B GoF mutation who have treatment resistant seizures and / or behavioral problems. At a later stage, children with other GoF GRIN related disorders (GRIN1, GRIN2A and GRIN2D) may also be included in the trial. 

Currently the trial is active in 4 trial sites in Europe: in Spain in Barcelona (San Joan de Déu Hospital) and Madrid (Hospital Ruber Internacional) and in the Netherlands in Rotterdam (Erasmus MC) and in Utrecht (Wilhelmina Children’s Hospital). 

More European Trial sites will be opened in the near future.

Currently the criteria for participation in the Honeycomb clinical trial are:

  • Children must be between 6 months and 12 years of age and must have GRIN2B gene variants known to result in GoF of the NMDA receptor.
  • Children should have at least one observable motor seizure per week and 4 or more observable motor seizures (generalized or focal) during the prospective 4-week observation period.
  • Seizure control must have failed with at least 2 antiseizure medications (
  • ASMs) used at appropriate dose and duration.
  • Alternatively, children must have significant behavioral and or motor symptoms based on caregiver report.

More detailed information on the Honeycomb Trial can be found at the following link: https://clinicaltrials.gov/ct2/show/NCT05818943?term=radiprodil&draw=2&rank=1

as well as in the following presentation: https://www.grineurope.org/wp-content/uploads/2023/05/Developing-Radiprodil-for-GRIN-related-Disorders.pdf

Research Projects

The GRINscale Project:

This project arose from the need to understand the major changes that happen in patients with GRIN disorders (GRINpathologies).

The wide variety and diversity of symptoms that this group of diseases represents, shows the need for an appropriate scale that measures all the relative complex changes each particular individual may undergo when facing any kind of treatment.

For this reason, the team of Dr. Angeles Garcia Cazorla, based on their current knowledge from the L-Serine trail, has started working on the development of a GRIN specific functional scale for the whole of GRINdisorders. To validate this scale Dr. Garcia Cazorla will collaborate with doctors from Spain and with other European partners, where they would share and validate these findings.

The project contemplates hiring a full time Neuropediatrician for 3 years to collect and coordinate the data and verify potential biomarkers that could define the factors associated with response to treatment. Development of specific clinical and biological markers is essential for future clinical trials.

If you want to contribute to this project, you can make your donation directly to the Sant Joan de Deu Hospital through this link: 

https://colabora.sjdrecerca.org/p2p/6967/Tu-eres-nuestra-fuerza

Gene therapies for GRIN disorder

This project, led by Amy Ramsey, brings together NMDA receptor neuroscientists with pediatric neurologists (including Dr. A. García Cazorla, who led the Serine clinical trial for GRIN disorder) and biotech researchers who specialize in gene therapy. The goal is to test the efficacy and tolerability of gene replacement as a strategy to treat GRIN disorder.

SFARI | Gene therapies for GRIN disorder

PUBLICATIONS

GRIN database: A unified and manually curated repertoire of GRIN variants.
García-Recio A, Santos-Gómez A, Soto D, Julia-Palacios N, García-Cazorla À, Altafaj X, Olivella M. Hum Mutat. 2020 Nov 30. doi: 10.1002/humu.24141. PMID: 33252190

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