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Finding a cure for GRIN disorders is on its way.
Since there are many GRIN genetic variations, each may require a tailored treatment, but there is cause for hope. Preliminary research on mice shows it is possible to reverse GRIN symptoms, even later in life. And because the NMDA receptor is involved in Alzheimer’s and other common diseases, it has become one of the most-studied areas in brain science.
Our mission to cure GRIN disorders
Our plan is to solicit applications from scientists around the world who are working on GRIN research, prioritizing work that will contribute directly to a cure. Over the short-term, we will be funding existing teams of researchers working on GRIN therapies, who are active in the following areas:
Creating animal models for GRIN disorders
An important tool in both basic and translational research is the production of animal models to study the disease and assess modes for intervention.
To date, no mice carrying human GRIN variants are available. We are in the process of producing mice with human mutations in GRIN genes, after signing a contract with the transgenic facility in the Weizmann Institute of Science. This highly prestigious institute has vast experience in genetically engineered mice and willing to assist us in our current research. We are in the process of designing two mice with two GRIN variants, and we are anticipating their availability in the coming months.
Developing assays for drug screening
The goal is constructing a cell-based assay to robustly screen millions of different drugs and chemicals. The assay will express the NMDA receptor in a way that is highly versatile and can be adapted to include any GRIN variant chosen. We are in the second stage of the project after the successful expression of the GRIN1 protein in cell culture.
The second stage is ongoing and involves the addition of the GRIN2 to form the full NMDA receptor. This will allow us to create and study any type of human GRIN genetic variant. When accomplished, we will conduct the drug/compound screen in an automated function, with estimated results in a matter of days/weeks.
The assay development is done in the laboratory of Professor Shai Berlin, located in the Neuroscience department in the Technion.
Patient-derived cells bank
In order to test drugs or gene therapies in a personalized-manner, we established a cell bank.
We obtained skin cells from several patients (different variants) for any future applications, including the production of Induced Pluripotent Stem Cells (iPSCs) and nerve cells (neurons). This work (and also the FDA approved drugs screening) is done with the help of Professor Miguel Weil, Academic Head of the High Throughput Screening and Biological Assays Unit, The BLAVATNIK Center for Drug Discovery in Tel Aviv University.
Screening of FDA approved drugs
Searching for existing FDA-approved drugs that can be used to treat the symptoms of certain GRIN disorders.
The screening will be done using a highly sophisticated automated system that scans thousands of candidates, by the laboratory of Professor Miguel Weil, Academic Head of the High Throughput Screening and Biological Assays Unit, The BLAVATNIK Center for Drug Discovery in Tel Aviv University.
Creating neurons and brain organoids from patients cells
As each child has a unique variant, it requires a tailored medicine for their particular mutation. The iPSCs technology allows generating customized disease modeling, using direct conversion methods from human somatic cells (e.g. from blood or skin samples) into desired cell types, such as neurons. Generations of iPSCs are a significant breakthrough in the neurodevelopmental field, as differentiation of patient-derived iPSCs into neurons may recapitulate cellular aspects of many neurological diseases. Our plan is to create neurons and brain organoids (mini brains) from skin cells and use them to find specific treatments. This work will be conducted at the laboratory of Professor Yaqub Hanna, a world expert in the field of stem cell biology, at the Weizmann Institute of Science.
Gene editing of GRIN variants
This is the most pioneering and critical work for curing GRIN disorders, currently executed with the assistance of Professor Dan Offen, head of the laboratory for Translational Neuroscience at Tel Aviv University. His laboratory is working on finding treatments for several brain disorders (Alzheimers disease, autism, ALS, and GRIN disorders) in different approaches: stem cell therapy, gene therapy including gene editing with CRISPR, and developing delivery systems to the brain with viral vectors and exosomes.
The laboratory has developed a novel method to target only the disease-causing variant while leaving the second normal gene intact. This highly sophisticated approach may be utilized to treat heterozygous patients suffering from conditions caused by single point mutations, with relevance to many different genetic diseases.
We are currently testing the feasibility of the method in a few different GRIN variants. We are using cutting edge genetic tools to restore the normal activity of the gene and reverse the genetic change. When the genetic correction is made, a functional analysis of the receptor will asses the successful restoration of GRIN gene function. The specific treatment will be tested directly on the patient’s nerve cells.
We are developing ways to reach the brain by various ways:
- AAVs (adeno-associated viruses): given intravenously to a candidate for gene therapy, since they do not cause human disease and can deliver genes into the brain. Over 100 human clinical trials using AAVs for gene therapy were conducted and those for retina and brain diseases (e.g. SMA, Parkinson’s disease) have shown great promise.
- Exosomes: emerging as efficient delivery agents of therapeutics and molecular information to the brain. Their natural ability to enter the brain can be combined with non-invasive and highly effective intranasal administration (through the nose), opening a new path for neurological and psychiatric medicine.
Both modalities will be tested on the different mice strains produced to mimic the human GRIN disorders and patients’ neurons.
Target: Screening of FDA-approved drugs.
Estimated time: Q3/2019.
Target: Generate iPSCs and form them into neurons and brain organoids. The production of patient-derived neurons and brain organoids which will serve as personalized disease models. For each child, a unique genetic correction will be designed. The correction will be tested on his/her specific disease model cells.
Estimated Time: Q2/2020.
Target: Gene editing of GRIN mice, using AAVs will be tested for efficiency and accuracy.
Estimated Time: Q3/2020.