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- Title
Quantification of human mature frataxin protein expression in nonhuman primate hearts after gene therapy.
- Authors
Rojsajjakul, Teerapat; Hordeaux, Juliette J.; Choudhury, Gourav R.; Hinderer, Christian J.; Mesaros, Clementina; Wilson, James M.; Blair, Ian A.
- Abstract
Deficiency in human mature frataxin (hFXN-M) protein is responsible for the devastating neurodegenerative and cardiodegenerative disease of Friedreich's ataxia (FRDA). It results primarily through epigenetic silencing of the FXN gene by GAA triplet repeats on intron 1 of both alleles. GAA repeat lengths are most commonly between 600 and 1200 but can reach 1700. A subset of approximately 3% of FRDA patients have GAA repeats on one allele and a mutation on the other. FRDA patients die most commonly in their 30s from heart disease. Therefore, increasing expression of heart hFXN-M using gene therapy offers a way to prevent early mortality in FRDA. We used rhesus macaque monkeys to test the pharmacology of an adeno-associated virus (AAV)hu68.CB7.hFXN therapy. The advantage of using non-human primates for hFXN-M gene therapy studies is that hFXN-M and monkey FXN-M (mFXN-M) are 98.5% identical, which limits potential immunologic side-effects. However, this presented a formidable bioanalytical challenge in quantification of proteins with almost identical sequences. This could be overcome by the development of a species-specific quantitative mass spectrometry-based method, which has revealed for the first time, robust transgene-specific human protein expression in monkey heart tissue. The dose response is non-linear resulting in a ten-fold increase in monkey heart hFXN-M protein expression with only a three-fold increase in dose of the vector. Species-specific quantitative mass spectrometry revealed robust human frataxin expression in monkey heart tissue after dosing with an AAV vector expressing frataxin and a non-linear increase in protein expression with increasing amounts of vector (248 characters).
- Subjects
FRATAXIN; PROTEIN expression; GENE therapy; FRIEDREICH'S ataxia; GENE expression; TRANSGENE expression
- Publication
Communications Biology, 2023, Vol 6, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-023-05472-z