The creatine deficiency syndrome (CDS), having the three specific disorders of guanidinoacetate methyltransferase (GAMT) deficiency, L-arginine: glycine amidinotransferase (AGAT) deficiency, and Creatine transporter (CRTR) deficiency, are classified as inborn errors of creatine synthesis and transport. Protheragen, as one of the leading preclinical research service providers focused on mitochondrial disorders, is spearheading therapy research and innovation of CDS.
Introduction to Creatine Deficiency Syndromes
Metabolic disorders resulting from mutations in the GATM, GAMT, and SLC6A8 genes are referred to as creatine deficiency syndromes (CDS) or CDD. These mutations are known to affect the enzymes and creatine transporters responsible for the synthesis of creatine. CDD primarily impacts the central nervous system. A defining symptom of this syndrome is a stark reduction of creatine and phosphocreatine levels in the brain. Most individuals show a combination of moderate intellectual disability, an extreme delay in acquiring language, and as well as epilepsy, behavioral disturbances, severe speech delays, and extrapyramidal syndrome. These pathologies are often diagnosed during the infant stage.
Fig.1 Cr synthesis and transport and its roles in Cr/PCr/CK system, neurotransmission and osmoregulation. (Fernandes-Pires, G., 2022)
Novel Diagnostic Methods of Creatine Deficiency Syndromes
Given the improvement of diagnostic technology, the expectation is that methods such as gene sequencing and biomarker analyses will increase the efficiency and accuracy of disease detection processes in the future.
Novel Diagnostic Methods of Creatine Deficiency Syndromes
Given the improvement of diagnostic technology, the expectation is that methods such as gene sequencing and biomarker analyses will increase the efficiency and accuracy of disease detection processes in the future.
Novel Therapies of Creatine Deficiency Syndromes
Currently, there are several developments toward improving existing modalities of therapeutic for CDS. Such new strategies include nose-to-brain drug delivery, pharmacochaperones therapy, and gene therapy with AAV vectors.
- Nose-to-brain Drug Delivery
This method employs the permeable nature of the nasal mucosa to enable direct delivery of drugs to the brain without having to cross the blood-brain barrier. In particular, animal studies using lipid nanovesicles containing a creatine derivative, dodecyl creatine ester (DCE), have shown great promise and may serve as a viable therapeutic option for SLC6A8 deficiency.
Fig.2 Nose-to-brain drug delivery in both the human and rodent brain. (Fernandes-Pires, G., 2022)
- Pharmacochaperones
Pharmacochaperones are microscopic molecules that can assist mutated proteins misfolded in a way that makes it possible for them to be placed in the correct area within a cell and their activity is restored. For instance, in the case of CDS, pharmacochaperones could potentially restore activity in the SLC6A8 mutations' variants and lead to the alleviation of symptoms.
Fig.3 Treatment by pharmacochaperones. (Fernandes-Pires, G., 2022)
- Gene Therapy
Gene therapy is the corrective therapeutic for genetic disorders that encompasses administering a viral vector containing a corrective gene into the individual's body. In the case of SLC6A8 deficiency within the context of CDS, gene therapy is intended to restore the functional expression of SLC6A8 transporter protein. Currently, adeno-associated viruses (AAV) are amongst the most used vectors in gene therapy because of their great safety record and poor ability to elicit an immune response. Using AAV vectors to deliver the corrective gene should increase the creatine level in the brain and reduce the manifestations.
Fig.4 AAV-based CNS treatment for SLC6A8 transporter by systemic or intrathecal injection. (Fernandes-Pires, G., 2022)
Our Services
The range of CDS research services offered by Protheragen is comprehensive and encompasses all the areas peculiar to the challenges posed by CDS. Our cutting-edge solutions focus on creating the best understanding and development in diagnosis and therapy.
Diagnostic Methods Development Services
The services we conduct in developing diagnostic methods are critical in detecting and validating the existence of creatine deficiency syndromes. Using advanced genetic testing, biochemical analyses, and neuroimaging methods of research, we offer detailed and complete diagnostic reports to aid in preclinical investigations.
Small Molecule Drug Development Service
We offer the following services to support your exploration of therapies for creatine deficiency syndromes.
Small Molecule Drug Development Service
Our innovative personnel focus on the design of small molecule therapeutics aimed at pathways associated with the synthesis or transport of creatine to restore levels of creatine and provide relief to neurological manifestations.
Gene Therapy Development Service
In treating CDS, gene therapy introduces therapeutic genes associated with creatine metabolism. In our comprehensive service for the development of gene therapy, we provide preclinical evaluation, vector design, and all other necessary steps.
Our Advantages
Protheragen proactively develops partnerships with academic institutions, biopharmaceutical companies, and individual advocacy groups in order to accelerate the development of novel therapeutics 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.
