Neonatal gene therapy achieves sustained disease rescue of maple syrup urine disease in mice

Abstract

Maple syrup urine disease (MSUD) is a rare recessively inherited metabolic disorder causing accumulation of branched chain amino acids leading to neonatal death, if untreated. Treatment for MSUD represents an unmet need because the current treatment with life-long low-protein diet is challenging to maintain, and despite treatment the risk of acute decompensations and neuropsychiatric symptoms remains. Here, based on significant liver contribution to the catabolism of the branched chain amino acid leucine, we develop a liver-directed adeno-associated virus (AAV8) gene therapy for MSUD. We establish and characterize the Bckdha (branched chain keto acid dehydrogenase a)−/− mouse that exhibits a lethal neonatal phenotype mimicking human MSUD. Animals were treated at P0 with intravenous human BCKDHA AAV8 vectors under the control of either a ubiquitous or a liver-specific promoter. BCKDHA gene transfer rescued the lethal phenotype. While the use of a ubiquitous promoter fully and sustainably rescued the disease (long-term survival, normal phenotype and correction of biochemical abnormalities), liver-specific expression of BCKDHA led to partial, though sustained rescue. Here we show efficacy of gene therapy for MSUD demonstrating its potential for clinical translation.

RNA‐binding motif protein 24 inhibits HBV replication in vivo

“…Plasmid‐mediated transient expression and AAV‐mediated long‐term expression strategies are generally used for regulating gene expression. AAV is a safe, persistent, and highly efficient gene therapy vector with low pathogenicity for human gene therapy 19 . A recombinant AAV‐RBM24 vector was constructed herein for the liver‐directed transduction of RBM24.…”

“…AAV is a safe, persistent, and highly efficient gene therapy vector with low pathogenicity for human gene therapy. 19 A recombinant AAV-RBM24 vector was constructed herein for the liver-directed transduction of RBM24. Compared to the controls, the administration of AAV-RBM24 did not induce obvious pathological damages in the heart, brain, lungs, kidneys, liver, and spleen (Figure 4E).…”

“…Adeno‐associated virus (AAV) is one of the most promising vectors for human gene therapy owing to their persistence, high efficiency, and lack of pathogenicity 19 . AAV‐8 can serve as a safe liver‐directed gene therapy vector for gene transduction 19 . In this study, a recombinant AAV8‐RBM24 (AAV‐RBM24) vector was successfully constructed, and its effect on hepatic functions and histopathology in mice was investigated.…”

“…RBM24 also reduced the levels of HBV cccDNA and other indicators of HBV in an rcccDNA mouse model. Adeno‐associated virus (AAV) is one of the most promising vectors for human gene therapy owing to their persistence, high efficiency, and lack of pathogenicity 19 . AAV‐8 can serve as a safe liver‐directed gene therapy vector for gene transduction 19 .…”

Treatment of maple syrup urine disease: Benefits, risks, and challenges of liver transplantation

“…New approaches are being studied for the adjuvant treatment of MSUD using antioxidant substances such as L‐carnitine (L‐car). It is possible that with a better understanding of the pathophysiology of the disease, including the mechanisms of brain damage involved, new therapeutic strategies will be developed that will enable a better prognosis for patients with MSUD (Guerreiro et al, 2015; Pontoizeau et al, 2022). L‐car deficiency can be very serious and cause deleterious effects on the CNS (Bahl & Bressler, 1989).…”