The creatine deficiency syndromes (CDS), which are inborn errors of creatine metabolism and transport, encompass three specific disorders, Guanidinoacetate methyltransferase (GAMT) deficiency, L-arginine: glycine amidinotransferase (AGAT) deficiency, and Creatine transporter (CRTR) deficiency. As a leading preclinical contract research organization (CRO) specializing in mitochondrial diseases, Protheragen is at the forefront of advancing research and innovation in CDS.
Introduction to Creatine Deficiency Syndromes
Creatine deficiency syndromes (CDS), also known as CDD, are inherited metabolic disorders caused by mutations in GATM, GAMT, and SLC6A8 genes, which encode enzymes and creatine transporters in the creatine synthesis pathway, primarily affecting the central nervous system (CNS). These syndromes are characterized by a depletion of creatine/phosphocreatine levels in the brain. Most patients exhibit varying degrees of intellectual disability and severe speech delay accompanied by epilepsy, extrapyramidal syndrome, and behavioral disturbances. These diseases are typically diagnosed during infancy.
Fig.1 Cr synthesis and transport and its roles in Cr/PCr/CK system, neurotransmission and osmoregulation. (Fernandes-Pires, G., 2022)
Research Progress of Creatine Deficiency Syndromes
The current research is focused on gaining insights into the genetics, biochemistry, clinical manifestations, and molecular mechanisms of the disease. Additionally, scientists are actively seeking novel treatments to enhance patients' quality of life and outcomes.
Novel Diagnostic Methods of Creatine Deficiency Syndromes
With the continuous advancement of diagnostic technology, it is anticipated that approaches such as gene sequencing and biomarker testing will enhance both the speed and precision of early disease detection.
Novel Therapies of Creatine Deficiency Syndromes
Several innovative approaches are currently being developed to enhance existing therapies for CDS. These novel strategies encompass nose-to-brain drug delivery, pharmacochaperones, and gene therapy utilizing AAV vectors.
- Nose-to-brain Drug Delivery
This approach utilizes the highly permeable nasal mucosa to facilitate direct drug delivery to the brain, circumventing the blood-brain barrier. Specifically, lipid nanovesicles encapsulating a creatine derivative known as dodecyl creatine ester (DCE) have demonstrated promising results in animal models and hold potential as an effective therapeutic strategy for addressing SLC6A8 deficiency.
Fig.2 Nose-to-brain drug delivery in both the human and rodent brain. (Fernandes-Pires, G., 2022)
- Pharmacochaperones
Pharmacochaperones are small molecules that have the potential to prevent or rectify misfolding of mutated proteins, thereby facilitating their proper localization within cells and potentially restoring their activity. In the case of CDS, pharmacochaperones may be able to restore function in mutated SLC6A8 variants, leading to an improvement in symptoms.
Fig.3 Treatment by pharmacochaperones. (Fernandes-Pires, G., 2022)
- Gene Therapy
Gene therapy involves the delivery of a corrective gene into a patient's body using viral vectors for the treatment of genetic diseases. Specifically, for CDS, particularly SLC6A8 deficiency, gene therapy aims to restore functional expression of the SLC6A8 transporter protein. Adeno-associated viruses (AAV) are commonly utilized as vectors in gene therapy due to their excellent safety profile and low immunogenicity. By delivering the corrective gene through AAV vectors, it is possible to restore creatine levels in the brain and ameliorate symptoms.
Fig.4 AAV-based CNS treatment for SLC6A8 transporter by systemic or intrathecal injection. (Fernandes-Pires, G., 2022)
Our Services
The comprehensive suite of CDS research services offered by Protheragen is specifically designed to address the unique challenges associated with CDS. Our cutting-edge solutions aim to enhance understanding and development in the fields of diagnosis and treatment.
Diagnostic Methods Development Services
Our diagnostic methods development services play a pivotal role in the identification and confirmation of creatine deficiency syndromes. Through cutting-edge genetic testing, biochemical analyses, and neuroimaging techniques, we provide precise and comprehensive diagnostic reports to guide preclinical research.
Therapeutics Development Services
We offer the following services to support your exploration of therapies for creatine deficiency syndromes.
Small Molecule Drug Development Service
Our experienced team specializes in the development of small-molecule drugs that target the pathways involved in creatine synthesis or transport, intending to restore creatine levels and alleviate neurological symptoms.
Gene Therapy Development Service
Gene therapy shows potential in treating CDS by delivering therapeutic genes involved in creatine metabolism. Our comprehensive gene therapy development service includes vector design, and preclinical evaluation to advance gene-based treatments for CDS.
Our Advantages
Protheragen actively seeks collaborative partnerships with academic institutions, biopharmaceutical companies, and patient advocacy groups to expedite the development of innovative treatments for creatine Deficiency Syndromes. If you are interested in our services, please feel free to contact us.
Reference
- Fernandes-Pires, G., & Braissant, O. (2022). Current and potential new treatment strategies for creatine deficiency syndromes. Molecular genetics and metabolism, 135(1), 15–26.
