Mutations in the GNAO1 gene of the G203R variant are the most aggressive form of the disease. Patients diagnosed with this variant experience the full spectrum of symptoms associated with the disease: from seizures to movement disorders of different types.
The image shows the GAO protein, encoded by the GNAO1 gene, and position 203 of the amino acid glycine which should be there instead of the amino acid arginine present in our children because of the mutation. This change causes a totally different structure of the protein and makes it unable to bind to the beta and gamma units to perform its function. A small change that changes everything.
As the mutations of this variant are in the core of the Gao protein, the change in chemical properties is total and the effect on patients is devastating.
A group of families from all over the world with the sole objective of saving the lives of our children affected by this G203R variant of the GNAO1 gene mutation.
Registered as a not-for-profit association in Spain
an incredible team of world-class scientists, determined to find drugs capable of neutralizing the toxic protein generated by our children’s mutation.
The road to treatment for our children goes through our friends at Perlara PBC. The world’s first company to guide families with rare diseases to viable treatments using a decentralized global network of laboratories and research teams working in a coordinated way. Meet our heroes.
PhD in molecular and cell biology from Harvard University and was a Lewis-Sigler Fellow at Princeton University. In 2014, Dr. Perlstein founded Perlara PBC, the first biotech public benefit corporation to co-develop drugs in collaboration with families and communities affected by genetic diseases. Throughout his tenure at the bench, Dr. Perlstein conducted research in genetics, cell biology, neuroscience, pharmacology, and drug discovery
Postgraduate fellow, with proven professional experience in the research industry and scientific communication. Keen on communicating research to the non-scientific community and reaching families in need. Skilled in Molecular biology, Protein Biology, Scientific writing and Genetic Counselling. Strong research professional with a PhD in neurodegenerative diseases from the University of Leicester,UK and a Post doctoral Fellow from the Tel Aviv University, Israel, specializing in DNA replication.
Group Leader, MRC London Institute of Medical Sciences, Imperial College London. Now working within the Behavioural Phenomics group with support from Syngenta my work focuses on movement in C. elegans exposed to drugs. Specifically, with the aim of identifying the mode of action of uncharacterised drugs by their shared effect on movement in relation to know ones.
Experienced geneticist and stem cell biologist with an interest in transcriptional networks in stem cells. Skilled in Molecular Biology, Cell Culture, RNA-Seq, Genomics, Cloning, Flow Cytometry, and Confocal Microscopy. Enthusiastic teacher and presenter for different audiences. Recipient of EMBO Long-Term Fellowship.
Translational research scientist from Columbia University Medical Center and the University of Minnesota, using high-throughput genomic, lipidomic, and metabolomic approaches to investigate human disease, human nutrition, molecular evolution, and functional biodiversity. Teacher and mentor that establishes classrooms and laboratories as interactive, intellectually fearless environments that inspire an enduring appreciation for the interconnectedness of disciplines within biology from the molecular to the organismal level.
The classical approach of a research aimed
at understanding the mechanisms of mutation in psynaptic processes, would simply not be applicable in our case.
Neither would the approach of gene editing therapies, since despite being the most definitive solution, a therapy of practical application is still far from being achieved and even today, the legal regulatory mechanisms are not yet established.
We are fighting a battle against time, the survival of our children is at stake and that is the reason why we are betting on the only real and applicable solution in a short period of time: Drug Repurposing screen created and developed by Perlara PBC
Drug repurposing involves using genetically modified animals that have the disease mutation in their genome. These animals will be exposed to thousands of FDA-approved drugs, clinical trial drugs and compounds from preclinical tools.
Based on the observation of the effects of each drug in the genetically modified animals, the objective is to find the drug or group of drugs that prove to be able to neutralize the toxic GAO protein generated by the mutation of our children.
Caenorhabditis elegans is the most studied animal in science and this project will use the G203R mutants developed by the Scripps Research Institute
in homozygous and heterozygous versions.
Their movement pattern will be the main
indicator for drug validation.
Fruit flies with the G203R mutation were developed at the University of Geneva. They will be used as a validation model on the results obtained from the tests
on yeast and worms. Their movement and
life expectancy will be analyzed
to validate candidate drugs as final step.
Although yeasts are quite different from humans, they possess their own version of GNAO1, called GPA1.
For this reason, they are the ideal type of organism
for this project, as they allow us to analyze
thousands of drugs by detecting defects
in their growth.
The GNAO1 G203R mutation is generated in several strands and then introduced into plasmids, which will carry the mutation into the genome of the animal model.
The genetically modified animals are grown to create the stock to be used for the screening process.
The Spectrum and LOPAC collections will be screened initially in yeast patient avatars. The Broad Repurposing Hub library is will be prepared with 6,000 to 8,000 compounds for the later rounds of testing.
Automated processes introduce each test compound on the mutant animals and record the effects of each drug. In yeasts, changes in their growth are observed, in other animals, the effects on their movement pattern and in flies their movement pattern and life expectancy
Post-screening analysis is performed to identify compounds that have been shown to have an effect on the animals and controls are performed to confirm success.
Documentation of the results and the list of drugs with proven effects on the mutation is made
If the resulting drugs are sufficiently safe, they are prescribed to patients. If, on the other hand, they present some toxicity, a new project is established to start clinical trials.
Treatment begins with the collaboration of local medical teams. The improvement of disease symptoms is monitored and all progress is documented.
The above steps will be developed for each of the animals used in the project in the following sequence. The results of the tests in each animal will determine how the analysis will be carried out in the next stage:
All results obtained at each stage of this project, will be freely shared with the scientific community.
Since thousands of drugs will be tested on such an important protein, the vision of Perlara PBC and its partners is that our results could be the start of many more investigations.
The families who are part of this project proudly share this vision.
are that the results obtained in this project can serve as a basis for future research to analyze the pharmacological mechanisms of the drugs applied.
This knowledge could be the basis for solving the other variants of the GNAO1 mutation and other rare genetic-based diseases.
The project is currently underway. The families have financed the costs of the first part of the research, but we need help to cover the costs of the next stages.
By funding this project you help save our children’s lives and open the door to helping many, many more lives. You help the scientific community to understand more about one of the most important proteins for the brain and to solve many more diseases.
Help us to save the lives of our children, give them the possibility of a full and happy life.
Help us to help and make history with us!
SWIFT: ES15 0182 0958 4102 0173 3284
BIC: BBVA ES MMXXX
Beneficiary: Asociación Acción GNAO1 / GNAO1 Action
Description: Donativo / Donation.
Or if you wish, Donation and your name to send you our gratitude.
We are accompanied by friends and institutions from all over the world in the adventure we are starting. Proud to share with them and Perlara PBC the path towards the improvement and hopefully a cure of our children.
Thank you…
to our friends of the GNAO1 Association of Finland for supporting this endeavor with their funds, which are entirely destined to this project.
for their help in the development of the yeast screening, especially to Andrew Munkacsi’s lab
for the generation of the screening drug library and its support for the research stage in worms