Recombinant Human Glutaryl Coenzyme A Dehydrogenase Replacement Therapy in Glutaric Aciduria Type 1 KO Mice

초록

Background : Glutaric aciduria type 1 (GA1) is a rare neuro-metabolic disorder result from deficiency of glutaryl-CoA dehydrogenase (GCDH). Early treatment with low lysine diet before the onset of neurological symptoms is important for prognosis. However, dietary restriction is a clinically difficult for children and their caregivers. Methods : This study was to investigate the effects of enzyme replacement therapy using recombinant human GCDH (rhGCDH) in the new strain of GA1 mice model prepared using CRISP/Cas9 technology. We proceeded with a two-step study design. We evaluate the traits of GCDH-/- mice, and we conduct single-dose intravenous (IV) and subcutaneous (SC) administration of rhGCDH in the GCDH-/- mice. Results : The GCDH-/- mice showed biochemical characteristics with increased GA concentrations in urine, brain, and liver tissue and abnormal findings of brain MRI, which was consistent with the GA1 phenotype. In the experiments on administering rhGCDH to GCDH-/- mice, it was possible to significantly reduce the urinary GA levels. Discussion : These results suggest that enzyme replacement therapy using rhGCDH has the potential to be a new treatment strategy for GA1.