In the spring of 2023, with funds raised by the CCDS community, ACD launched the first ever Creatine Deficiency Research Center (CDRC) at the University of Utah. Under the mentorship of Drs. Nicola Longo and Marzia Pasquali, the first of several planned projects was launched by Dr. Steven Baker. To learn more about the Baker Lab and the research being done to find a potential therapy for Creatine Transporter Deficiency, you may view his live interview conducted Fall of 2022, his progress update shared August of 2023, or read more on Baker’s lab page (hint: be sure to click each of the tabs up top).
ClinGen Collaborations
The Clinical Genome Resource (ClinGen) is an effort funded by the National Institutes of Health (USA) dedicated to determining the clinical relevance of genes and variants for use in precision medicine and research.
ClinGen’s Genome Connect
The Association for Creatine Deficiencies is working with Geisinger, a ClinGen grantee to share genetic and health information from the ACD registry and increase our understanding of genomics. Through their existing registry, ACD is participating in the Patient Data Sharing Program to have certified genetic counselors review and share participants’ de-identified genetic and health information. Registry participants are able to direct whether or not they would like their de-identified data shared. Data sharing can help us better understand the relationship between genetics and health, clarify uncertain genetic testing results, and provide more information about a condition to inform treatment and management. Through data sharing, individual registry participants also can choose to receive updates about their genetic testing results.
ClinGen CCDS Variant Curation Expert Panel
Understanding the clinical significance of genetic variants is important to the integration of genomic medicine in healthcare. ClinGen has assembled a group of experts to generate gene-specific guidelines to determine the clinical significance of variants in the genes involved in CCDS. This group, called the ClinGen CCDS Variant Curation Expert Panel (VCEP) (https://clinicalgenome.org/affiliation/50047/), uses their guidelines to classify variants in each of the three CCDS genes and then submits the classifications and supporting data to publicly available variant databases, including ClinVar and the ClinGen Evidence Repository. The Food and Drug Administration (USA) approved ClinGen’s VCEP process in December 2018. In order facilitate variant classification by the ClinGen CCDS VCEP, the ACD is sharing genetic and phenotypic data with the group. This increased understanding of genetic variants expedites the molecular diagnosis of CCDS, thereby supporting early clinical intervention and development of targeted therapies.
CCDS Gene Therapy Consortium
Gene therapy is an exciting research area that holds the promise for treatments in many rare diseases. Both Creatine Transporter Deficiency and GAMT deficiency are monogenic conditions which makes them, in theory, good candidates for gene therapy. However, gene therapy efforts often require large financial investments and long timelines. As a first step, in 2019, ACD ran a fundraising campaign to fund the advancement of gene therapy for CCDS. With $50,000 raised by parents and families to be used towards gene therapy research efforts, the ACD started CCDS Gene Therapy Consortium. The mission of the consortium is to facilitate the timely sharing of information and development tools among the several labs that are pursuing gene therapies for creatine deficiencies. We believe that by building a collaborative environment and supporting through small grants shareable tools we can shorten the timeline and effort required to find gene therapy solutions for creatine deficiencies. For more updates click here.
ClinGen References
Savatt, J.M., Azzartiti, D.R, Faucett, W.A., Florin, J., Ledbetter, D.H., Miller, V.R., Palen, E., Rehm, H., Rhode, J., Rogers, L., Talbird, S., Trutoiu, L., Vidal, J.A., Waggoner, C., Riggs, E.R., Martin, C.L. Expanding Patient Data Sharing: GenomeConnect’s Pilot to Engage External Registries in Data Sharing. Poster presentation. Presented at the 38th Annual Education Conference for the National Society of Genetic Counselors, November 6, 2019, Salt Lake City, Utah.
Savatt, J.M, Azzartiti, D.R, Faucett, W.A., Ledbetter, D.H., Miller, V.R., Palen, E., Rehm, H., Rhode, J., Rogers, L., Talbird, S., Trutoiu, L., Vidal, J.A., Riggs, E.R., Martin, C.L. ClinGen’s Patient Data Sharing Program: Leveraging Data Sharing Experience from GenomeConnect to Broaden Patient Data Sharing Efforts. Poster Presentation. Curating the Clinical Genome Meeting. May 30, 2019. Washington, DC.
AGAT-Inhibitors Drug Development Research Project
Principal Investigator Dr. Nicola Longo, University of Utah
ACD is pleased to announce their support of Dr. Nicola Longo in his research into new treatments and therapies for Guanidinoacetate Methyltransferase (GAMT) Deficiency. $25,000 of the funds raised from Holiday Heroes 2020 have been dedicated to this research initiative. Presently, treatment for GAMT patients involves supplementing creatine and l-ornithine orally (between 400 and 800 mg/kg per day), an arginine-restricted diet with or without medical food, and sodium benzoate (100 mg/kg per day) to reduce the concentration of guanidinoacetate. Even with the best available therapy, the concentration of guanidinoacetate remains elevated above normal. The toxicity of guanidinoacetate is the likely cause of the incomplete response of GAMT deficiency to existing therapies and the poor response of seizures to anticonvulsivants. Dr. Longo has submitted a proposal to discover an inhibitor of the synthesis of guanidinoacetate, which would normalize the guanidinoacetate concentration in GAMT patients. These novel drugs, given with creatine supplements, should normalize the brain chemistry of GAMT patients, thus reducing the frequency of seizures and facilitating intellectual development. To learn more about this research, click here or watch Dr. Longo’s presentation at the CCDS 2020 Virtual Conference.
Past Projects
2021 ACD Fellowships
On February 1, 2021, the ACD announced three newly established ACD Fellowships totaling $90,000 that will fund early career researchers. Dr. Charles Kuntz (in the lab of Dr. Jonathan Schlebach), Dr. Peter Axerio-Cilies (in the lab of Dr. Sylvia Stockler), and Alex Lee (in the lab of Dr. Andreas Schulze) have been selected to each receive a $30,000 ACD Fellowship Award for 2021-2022. The overarching goal of the ACD Fellowship program is to fund opportunities which have the potential for translational success. To this end, each of the awardees is focused on advancing therapeutic discoveries for creatine deficiency disorders.
About Dr. Charles Kuntz
Charles Kuntz obtained a PhD in molecular pharmacology at Purdue University in 2015, applying computational approaches to study ligand binding mechanisms at the serotonin transporter. His work in Prof. Jonathan Schlebach’s laboratory at Indiana University focuses on molecular modeling and data science approaches utilized towards the study of the effects of mutational tolerance on membrane protein homeostasis. He will apply this experience towards identifying novel compounds that correct folding defects caused by deletion and missense mutations in the SLC6A8 gene.
About Schlebach Lab
The Schlebach lab was founded in 2016 at Indiana University Bloomington, and specializes in the application of emerging genetic, biochemical, and computational techniques in order to gain insights into the molecular basis of membrane protein misfolding diseases. Their lab seeks to draw from perspectives on the pharmacology of related genetic diseases in order to work towards the discovery of therapeutics for creatine transporter deficiency (CTD). With this award, Dr. Schlebach (Principle Investigator) and Dr. Kuntz (Postdoctoral Fellow) will work together to discover and validate drug candidates that correct the defects caused by a broad spectrum of CTD mutations in the SLC6A8 gene.
About Dr. Peter Axerio-Cilies
Peter received his Ph.D. in Experimental Medicine from the University of British Columbia, where he discovered and developed novel treatments for stroke and other neurological diseases. He has generated several lead drug prototypes for various protein targets associated with prostate cancer, stroke, neurological disorders, rare genetic diseases and infectious diseases. He has recently designed and implemented a drug discovery pipeline for the development of innovative neurological therapies for rare genetic diseases, including various creatine transporter (aka. SLC6a8) variants found in patients.
About Dr. Sylvia Stockler
Dr. Stockler is a Professor of Pediatrics at the Department of Pediatrics at (UBC) and head of the Division for Biochemical Genetics at BC Children’s Hospital. She authored the first description of GAMT and AGAT deficiency and has published several articles on cerebral creatine deficiency syndromes. Her research focuses on diagnosis and treatment of genetic conditions causing intellectual disability as well as on the evaluation of outcomes of treatment outcomes using innovative trial methodologies and outcome measures.
About Alex Lee
Alex Lee is a grad student in the Schulze Lab. Prior to starting his graduate studies, he completed his BSc at the University of. Toronto where he majored in neuroscience and molecular biology. His current research in the lab focuses on studying how creatine acts to regulate the expression of AGAT and the mechanism by which this occurs.
About Dr. Andreas Schulze
Dr. Andreas Schulze is a well-established Clinician Scientist who has spent the past 25+ years of medical research and clinical care in the field of Inborn Errors of Metabolism. Dr. Schulze leads a research groupthat appliesbiochemistry, genomics, cell biology, and model systems to improve the understanding of and develop treatments for rare inborn errors of metabolism. The main focus is on Creatine Deficiency Syndromes and Guanidinocompound-/ Arginine metabolism and Sanfilippo Syndrome.
