Successful treatment of severe MSUD in Bckdhb^−/− mice with neonatal AAV gene therapy

Abstract

Maple syrup urine disease (MSUD) is rare autosomal recessive metabolic disorder caused by the dysfunction of the mitochondrial branched‐chain 2‐ketoacid dehydrogenase (BCKD) enzyme complex leading to massive accumulation of branched‐chain amino acids and 2‐keto acids. MSUD management, based on a life‐long strict protein restriction with nontoxic amino acids oral supplementation represents an unmet need as it is associated with a poor quality of life, and does not fully protect from acute life‐threatening decompensations or long‐term neuropsychiatric complications. Orthotopic liver transplantation is a beneficial therapeutic option, which shows that restoration of only a fraction of whole‐body BCKD enzyme activity is therapeutic. MSUD is thus an ideal target for gene therapy. We and others have tested AAV gene therapy in mice for two of the three genes involved in MSUD, BCKDHA and DBT. In this study, we developed a similar approach for the third MSUD gene, BCKDHB. We performed the first characterization of a Bckdhb−/− mouse model, which recapitulates the severe human phenotype of MSUD with early‐neonatal symptoms leading to death during the first week of life with massive accumulation of MSUD biomarkers. Based on our previous experience in Bckdha−/− mice, we designed a transgene carrying the human BCKDHB gene under the control of a ubiquitous EF1α promoter, encapsidated in an AAV8 capsid. Injection in neonatal Bckdhb−/− mice at 1014 vg/kg achieved long‐term rescue of the severe MSUD phenotype of Bckdhb−/− mice. These data further validate the efficacy of gene therapy for MSUD opening perspectives towards clinical translation.

Oral enzyme therapy for maple syrup urine disease (MSUD) suppresses plasma leucine levels in intermediate MSUD mice and healthy nonhuman primates

“…Liver transplant has shown promise in attenuating symptoms and helping normalize BCAA homeostasis and may be an option for some patients 32,33 . The benefits observed in some patients with liver transplant suggest that liver‐directed gene therapy also may hold promise as a treatment for MSUD 34,35 . Ultimately, an interventional therapy that alleviates the lifelong burden of dietary restrictions and concomitantly prevents or treats metabolic decompensation episodes would drastically improve patient morbidity and quality of life.…”

Liver‐directed gene therapy for inherited metabolic diseases

“…A single AAV vector infusion in neonatal MSUD mice, with either E1α or E1β defects, resulted in long-term survival of the animals and rescue of the disease phenotype. 70,71 Liver-restricted gene transfer by a liver-specific promoter provided partial correction of the MSUD phenotype, suggesting that extrahepatic expression of the enzyme is needed to achieve full therapeutic efficacy. Long-term disease rescue was indeed obtained with an ubiquitous promoter, consistent with the branched-chain amino acid oxidation that takes place in several tissues, especially the muscle.…”

“…In the classical severe form of MSUD, with less than 3% residual enzyme activity, leucine accumulation causes coma and cerebral edema shortly after birth with early death in the absence of aggressive and timely management. A single AAV vector infusion in neonatal MSUD mice, with either E1α or E1β defects, resulted in long‐term survival of the animals and rescue of the disease phenotype 70,71 . Liver‐restricted gene transfer by a liver‐specific promoter provided partial correction of the MSUD phenotype, suggesting that extrahepatic expression of the enzyme is needed to achieve full therapeutic efficacy.…”

Mission possible: Gene therapy for inherited metabolic diseases

“…Chuecos and Lagor introduce AAV, which represent currently the leading liver‐targeting gene therapy technology, with a particular focus on AAV physiology, AAV transduction including sex differences and an updated review of AAV clinical trials for liver IMDs and their contribution to the field of gene therapy 8 . Pontoizeau et al provide an additional proof of concept of neonatal gene therapy for maple syrup urine disease 9 . Duff et al review the specificities, development and perspectives of gene therapy for urea cycle defects 10 .…”

“…8 Pontoizeau et al provide an additional proof of concept of neonatal gene therapy for maple syrup urine disease. 9 Duff et al review the specificities, development and perspectives of gene therapy for urea cycle defects. 10 Chandler and Venditti summarise the preclinical studies and clinical trials of genetic therapies developed for methylmalonic and propionic acidaemias and lessons learned over the years.…”