Aleksander Bogoniewski: “Unraveling SLC6A8 creatine deficiency: Insights into Neurodevelopment through Organoid Research”
SHORT SUMMARY
SLC6A8 creatine transporter deficiency has no effective treatments and continues to impact patients and their families. We are working to develop new models to study the intricacies of this disorder including 3D “mini brains” (organoids) and neurons with the goal of testing a corrective gene therapy. Preliminary results indicate that a virus carrying a promoter that is expressed in every cell has a higher creatine uptake compared to a neuron specific promoter. Additionally, SLC6A8 patients had organoids that grew to a larger size, suggesting a more immature developmental state. We will continue testing our gene therapy and culture systems to further understand this disorder.
ABSTRACT
The discovery of the first mutation in the SLC6A8 creatine transporter gene marked a significant advancement in understanding the pathophysiology of X-linked neuronal impairments with an unknown etiology. The absence of functional SLC6A8 creatine transporters results in inadequate uptake of the high-energy metabolite creatine into the brain, causing a spectrum of neurodevelopmental delays including intellectual disability, epilepsy, and behavioral disorders. Conventional therapeutic approaches, such as oral creatine supplementation, are ineffective due to the inability of patients with SLC6A8 mutation to facilitate cerebral creatine transport, leaving a significant therapeutic void and lack of symptom relief. Furthermore, there is a significant lack of knowledge regarding the cerebral development of individuals afflicted with SLC6A8 creatine transporter deficiency. Our research aims to address this gap by examining the developmental processes underlying SLC6A8 mutations using cerebral organoids and evaluating a range of adeno-associated virus (AAV)-mediated therapeutic interventions aimed at increasing cerebral creatine levels. Preliminary findings from our laboratory reveal a notable acceleration in the growth rate of cerebral organoids from individuals with SLC6A8 mutations compared to CRISPR-corrected isogenic controls. Subsequent investigations into AAV vectors will extend these observations to murine models and continue to explore organoid models through comprehensive transcriptome analyses, RNA sequencing, and advanced electrophysiological assessments. Through our multidisciplinary approach encompassing stem cell biology, gene therapy, and neurodevelopmental research, we aim to bridge the therapeutic gap and advance treatment paradigms for individuals affected by SLC6A8 creatine transporter deficiency.