The Association for Creatine Deficiencies (ACD) is playing an active role in funding research to find a cure and treatment for Cerebral Creatine Deficiency Syndromes (CCDS), and a cornerstone of this effort is the ACD Fellowship program.The overarching goal of the ACD Fellowship program is to fund opportunities led by early-career researchers which have the potential for translational success, leading to clinical trials for creatine deficiency treatments. With funding awarded at the beginning of the year in 2022, four fellowship projects conducted creatine deficiency research in 2022. Following are updates on each of these projects and their work completed in the last year:
Lea Broca-Brisson, University Paris-Saclay, France
Under supervision of Dr. Aloise Mabondzo, the ACD fellowship project by Lea Broca-Brisson and her team over the past year focused on using brain organoids to research Creatine Transporter Deficiency (CTD) at University Paris-Saclay in France. By reprogramming a patient’s blood or skin cells into induced pluripotent stem cells, researchers can coax them to differentiate into different types of cells. Using this method, one can create the equivalent of a ‘brain in a dish’- a three dimensional tissue structure that has the same types of cells that are present in the human brain. These are referred to as brain organoids. Traditionally, studies on the brain were limited to mouse models or postmortem studies of the human brain. Organoid technology presents an advantage as it allows one to study a complex organ such as the brain in a dish while preserving the complexity and human physiological context. Lea Broca-Brisson and her team succeeded in creating the first human brain organoid from CTD patients’ cells. This resulted in a high-fidelity model allowing for in-depth cellular and molecular research into CTD. Lea Broca-Brisson and her team used the brain organoids derived from different SLC6A8 patient iPSCs to better understand the mechanisms underlying CTD. Further, the team was able to identify biomarkers specific to CTD. This finding may have application in measuring the efficacy of potential treatments in the future. In the next phase of their work, they will be continuing to expand and characterize the discovered biomarkers in brain organoids bearing different SLC6A8 patient mutations.
“Finding the pathways of biomarker alteration for delivering effective medicine to the brain of patients suffering from creatine transporter deficiency,” said Broca-Brisson. “We would like to thank ACD for financial support which is of great importance for the development of our research program dealing with the development of brain organoids from patients with Creatine Transporter Deficiency.”
Dr. Peter Axerio-Cilies, BC Children’s Hospital Research Institute, Vancouver
Dr. Peter Axerio-Cilies and his team are working on the generation of a drug-repurposing pipeline in the lab of Dr. Sylvia Stockler at BC Children’s Hospital Research Institute in Vancouver, Canada. A drug-repurposing pipeline aims to find treatments for a disease using already approved drugs. This has a huge advantage over developing new drugs, since many repurposable drugs have already been developed for use in humans for another disease indication, there is limited need to conduct safety studies and identify the best route of delivery, so these can be brought to market faster. Dr. Axerio-Cilies and his team are working to find approved drugs that could restore creatine transporter functionality across different SLC6A8 mutations. Within their drug screening, the researchers have studied SLC6A8 channels bearing different mutations and identified known drugs that partially restore creatine transporter function for a subset of SLC6A8 mutations. This work has been conducted in cell lines engineered to express mutant SLC6A8. In next steps, The researchers plan to study patient-derived fibroblasts obtained from the Coriell repository. They will evaluate if the patient-derived cells show increased levels of creatine in response to exposure to the drugs. Eventually, researchers hope to find a clinical treatment for CTD using this strategy.
Axerio-Cilies shared, “We have made important strides towards understanding the requirements for potential drugs that restore the function of a variety of dysfunctional SLC6A8 variants. With our current progress and the continued generous support from the ACD community, we are excited and confident about making great advancements towards finding new treatment options for those with CTD.”
Dr. Charles Kuntz, University of Indiana, Bloomington
Dr. Charles Kuntz, in the lab of Dr. Jonathon Schlebach at the University of Indiana, Bloomington in the United States, has also focused on CTD drug repurposing with a project aiming to develop a therapy that restores the creatine transporter function in CTD patients. In silico, or virtual, screening efforts have led to several drug candidates which are now being examined for their efficacy in restoring creatine transporter expression. The researchers are looking into drugs that can rescue expression of the misfolded creatine transporter by stabilizing its structure. This is because misfolded proteins are unstable and get degraded within the cell quickly. But by stabilizing a misfolded protein, one can enhance its longevity and this in turn may help restore some function of the transporter. The next phase of the Schlebach Lab’s work is on testing some of the drug compounds discovered from the virtual screening efforts on cell lines from different SLC6A8 mutations.
According to Schlebach, “In the past year we have developed and applied new drug discovery methods to try to find new compounds that can restore function to creatine transporter mutants. Our efforts yielded a new panel of exciting drug candidates that we are currently working to experimentally characterize. We are optimistic that 2023 will be the year where we find potential therapeutics.”
Alex Lee, University of Toronto
In the lab of Dr. Andreas Schulze at University of Toronto in Canada, Alex Lee’s ACD fellowship project has focused on L-Arginine:Glycine Amidinotransferase (AGAT) Deficiency. Lee and Dr. Schulze are researching how creatine controls the amount of AGAT enzyme in cells. Because AGAT is an enzyme involved in the synthesis of creatine, it’s been thought that excess creatine in a normal cell may regulate the expression of AGAT and thereby control the level of synthesis of creatine- like in a feedback cycle. If we understand how AGAT expression is regulated by creatine, it may unveil other methods to turn on creatine expression where needed. This type of work is foundational in enabling us to understand how cells make changes at the RNA and protein level in response to creatine. Doing more research into this opens possibilities for new research into potential treatments to correct cellular creatine depletion and control the cells’ creatine content.
“The research of my group on better understanding of and treatment for creatine deficiency syndromes has become such an amazing undertaking that is leading us deeper and deeper into very basic questions of nature and evolution,” said Schulze. “My research group and I are grateful for the huge support that we are getting from the ACD community that allows us to continue this exciting journey.”
The ACD Fellowship program was created with the goal to grow lifelong research interest in CCDS among young investigators, helping to grow our collaborative community as well as bring new, exciting views to light on CCDS research possibilities. As fellows complete their research, their projects may be supported by additional funding from the ACD or other sources yet to be announced. “We are grateful for the hard work of these fellowship recipients and look forward to collaborating with them for years to come,” said ACD Executive Director Heidi Wallis.
