Abstract
Urea cycle disorders (UCD) are inherited defects in clearance of waste nitrogen with high morbidity and mortality. Novel and more effective therapies for UCD are needed. Studies in mice with constitutive activation of autophagy unravelled Beclin‐1 as druggable candidate for therapy of hyperammonemia. Next, we investigated efficacy of cell‐penetrating autophagy‐inducing Tat‐Beclin‐1 (TB‐1) peptide for therapy of the two most common UCD, namely ornithine transcarbamylase (OTC) and argininosuccinate lyase (ASL) deficiencies. TB‐1 reduced urinary orotic acid and improved survival under protein‐rich diet in spf‐ash mice, a model of OTC deficiency (proximal UCD). In AslNeo/Neo mice, a model of ASL deficiency (distal UCD), TB‐1 increased ureagenesis, reduced argininosuccinate, and improved survival. Moreover, it alleviated hepatocellular injury and decreased both cytoplasmic and nuclear glycogen accumulation in AslNeo/Neo mice. In conclusion, Beclin‐1‐dependent activation of autophagy improved biochemical and clinical phenotypes of proximal and distal defects of the urea cycle.
Highlights
In a previous study (Soria et al, 2018), we showed that rapamycin reduces orotic acid in spf-ash mice, a mouse model of the ornithine transcarbamylase (OTC) deficiency that carries a single nucleotide mutation in the fourth exon of the Otc gene resulting in a splicing defect and 10% of residual enzyme activity (Hodges & Rosenberg, 1989)
We investigated ammonia detoxification by measurements of blood ammonia levels during acute hyperammonemia induced by an ammonia challenge
Consistent with previous findings (Soria et al, 2018), gain-of-function mutation of the autophagy activator Becn1 protects against acute hyperammonemia in vivo, suggesting that Beclin-1 is a druggable candidate for therapy of hyperammonemia
Summary
Liver autophagy was recently found to support ammonia detoxification by furnishing the urea cycle with intermediates and energy that increase urea cycle flux under conditions of excessive ammonia (Soria et al, 2018). Liver-specific deficiency of autophagy impaired ammonia detoxification whereas its enhancement resulted in increased urea synthesis and protection against hyperammonemia (Soria et al, 2018). Drugs enhancing autophagy have potential for treatment of urea cycle disorders (UCD) (Soria & Brunetti-Pierri, 2018, 2019). Tat-Beclin-1 (TB-1) is an engineered cellpermeable peptide that potently and induces autophagy (Shoji-Kawata et al, 2013). TB-1 is formed by the HIV-1 Tat protein transduction domain attached via a diglycine linker to a peptide derived from Beclin-1 (Becn1), a key component of the autophagy induction machinery (Shoji-Kawata et al, 2013). TB-1 is an attractive therapeutic candidate for its specificity and at least in mice, it has shown great potential for treatment of various diseases, including several types of cancer, infections, cardiac dysfunction, skeletal disorders and axonal injuries
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