The Role of Preclinical Models in Creatine Transporter Deficiency: Neurobiological Mechanisms, Biomarkers and Therapeutic Development

Abstract

Creatine (Cr) Transporter Deficiency (CTD) is an X-linked metabolic disorder, mostly caused by missense mutations in the SLC6A8 gene and presenting with intellectual disability, autistic behavior, and epilepsy. There is no effective treatment for CTD and patients need lifelong assistance. Thus, the research of novel intervention strategies is a major scientific challenge. Animal models are an excellent tool to dissect the disease pathogenetic mechanisms and drive the preclinical development of therapeutics. This review illustrates the current knowledge about Cr metabolism and CTD clinical aspects, with a focus on mainstay diagnostic and therapeutic options. Then, we discuss the rodent models of CTD characterized in the last decade, comparing the phenotypes expressed within clinically relevant domains and the timeline of symptom development. This analysis highlights that animals with the ubiquitous deletion/mutation of SLC6A8 genes well recapitulate the early onset and the complex pathological phenotype of the human condition. Thus, they should represent the preferred model for preclinical efficacy studies. On the other hand, brain- and cell-specific conditional mutants are ideal for understanding the basis of CTD at a cellular and molecular level. Finally, we explain how CTD models might provide novel insight about the pathogenesis of other disorders, including cancer.

Monogenic developmental and epileptic encephalopathies of infancy and childhood, a population cohort from Norway

“…The patient phenotype at the age of 22 was in accordance with previous reports, except that she had also had primary amenorrhea.The SLC6A8 -gene codes for a sodium- and chloride-dependent transporter carrying creatine across the blood-brain-barrier. A reduced or lack of function of this transporter is suspected to be the reason why dietary supplementation of creatine and amino acids has shown limited success to rescue creatine levels in the CNS, and furthermore explains the limited efficiency to relieve symptoms ( 55 , 56 ). Patient 13 did not show any significant improvement in symptoms after initiation of treatment.…”

“…Patient 13 did not show any significant improvement in symptoms after initiation of treatment. There are promising ongoing studies on several new treatment strategies that may change the future treatment for these patients, including nose-to-brain delivery of medication, pharmacochaperones and gene therapy ( 55 , 56 ).…”

Stabilized Reversed Polymeric Micelles as Nanovector for Hydrophilic Compounds

“…These neurodevelopmental conditions share a common clinical picture presenting with low creatine levels, developmental delay, intellectual disability, autistic-like behavior, epilepsy, but also a plethora of non-neurological symptoms, including heart, muscle, and gastrointestinal problems [ 45 , 46 , 47 , 48 ]. Since dietary supplementation of creatine leads to the attenuation of symptoms in AGAT (AGAT-D) and GAMT deficiency (GAMTD-D, [ 47 , 48 ]), and fails to restore creatine levels in CRT deficiency (CRT-D) [ 27 ], our polymeric nanovectors might represent an important tool to i) optimize the biodistribution and half-life of creatine in AGAT-D and GAMTD-D patients; ii) devise an effective therapeutic strategy for CRT-D. Indeed, loading creatine in micelles would allow the cellular uptake of the molecule even in absence of its specific transporter.…”

“…Such requirements are met by dimethyl carbonate/water and chloroform/water pairs. Water is fully miscible in dimethyl carbonate (DCM) up to 3.32% in weight [ 27 ] and up to 0.08% in chloroform (CHL) [ 29 , 30 ].…”

“…Then, we developed a chemical strategy to crosslink the reversed micelles and freeze the structure, to avoid micelle disaggregation upon dilution and other additional aggregation phenomena, typical of non-stabilized micelles. At the end, we assessed the capabilities of loading and release of the produced system using creatine, a small hydrophilic molecule of therapeutic relevance for a group of neurodevelopmental disorders [ 27 , 28 ], as a testbed.…”