Long-Term Sex-Biased Correction of Circulating Propionic Acidemia Disease Markers by Adeno-Associated Virus Vectors

Abstract

Propionic academia (PA) occurs because of mutations in the PCCA or PCCB genes encoding the two subunits of propionyl-CoA carboxylase, a pivotal enzyme in the breakdown of certain amino acids and odd-chain fatty acids. There is no cure for PA, but dietary protein restriction and liver transplantation can attenuate its symptoms. We show here that a single intravenous injection of adeno-associated virus 2/8 (AAV8) or AAVrh10 expressing PCCA into PA hypomorphic mice decreased systemic propionylcarnitine and methyl citrate for up to 1.5 years. However, long-term phenotypic correction was always better in male mice. AAV-mediated PCCA expression was similar in most tissues in males and females at early time points and differed only in the liver. Over 1.5 years, luciferase and PCCA expression remained elevated in cardiac tissue for both sexes. In contrast, transgene expression in the liver and skeletal muscles of female, but not male, mice waned—suggesting that these tissues were major sinks for systemic phenotypic correction. These data indicate that single systemic intravenous therapy by AAV vectors can mediate long-term phenotype correction for PA. However, tissue-specific loss of expression in females reduces efficacy when compared with males. Whether similar sex-biased AAV effects occur in human gene therapy remains to be determined.

Enhanced liver gene transfer and evasion of preexisting humoral immunity with exosome-enveloped AAV vectors

“…Female mice were also treated with exo-or standard AAV8 vectors to provide a more stringent test to the technology, as several studies indicate that the liver of female mice is refractory to AAV vector transduction. [24][25][26] Also in this case, higher (approximately fourfold) circulating hF.IX transgene plasma levels were observed with exo-AAV8 vectors (Figure 2A). Interestingly, female mice treated with exo-AAV8 vectors showed comparable hF.IX transgene expression levels to male mice treated with standard AAV8 vectors (46 6 4 mg/mL vs 89 6 22 mg/mL at week 6, respectively, P 5 .5317; Mann-Whitney U test; Figure 2A).…”

AAV gene therapy corrects OTC deficiency and prevents liver fibrosis in aged OTC-knock out heterozygous mice

“…17 This is consistent with previous reports on gender differences in AAV gene transfer in murine liver. 6, 30, 31 …”

Pathophysiology of propionic and methylmalonic acidemias. Part 2: Treatment strategies

“…In a subsequent study, it was demonstrated that AAV‐mediated expression of Pcca resulted in long‐term phenotypic correction, although transgene expression decreased in the liver and in skeletal muscle. Surprisingly, tissue‐specific loss of expression was only present in females …”

“…Surprisingly, tissue-specific loss of expression was only present in females. 70 Next to gene therapy, there are more efforts to increase enzyme activity of PA and MMA patients. For patients harboring nonsense mutations, some drugs may promote premature termination codon read-through.…”