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Towards metabolic sink therapy for mut methylmalonic acidaemia: Correction of methylmalonyl‐CoA mutase deficiency in T lymphocytes from a mut methylmalonic acidaemia child by retroviral‐mediated gene transfer
Author(s) -
Chang C.C.,
Hsiao K.J.,
Lee Y.M.,
Lin C.M.
Publication year - 1999
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1023/a:1005593605399
Subject(s) - mutase , haematopoiesis , methylmalonic acidemia , methylmalonic acid , stem cell , biology , adenosylcobalamin , chemistry , biochemistry , endocrinology , microbiology and biotechnology , cofactor , gene , vitamin b12 , enzyme
The pathology associated with mut methylmalonic acidaemia (MMA) is caused by systemic accumulation of methylmalonate. Therefore, removal of methylmalonate from the circulation of affected individuals by an engineered metabolic system is proposed as a potential treatment. The haematopoietic cell is a potential site for such a metabolic system because of its direct contact with the accumulated metabolite and the demonstrated safety and ease in utilizing this cell. In this study, we assessed the feasibility of developing a haematopoietic cell‐based methylmalonate sink by analysing propionate/methylmalonate metabolism in a variety of haematopoietic cells. The results show that propionate metabolism and methylmalonyl‐CoA mutase (MCM) activity are intact in primary T cells, EBV‐B cells, and CD34 + haematopoietic stem cell‐derived granulocytes, whereas they are defective in those from a mut MMA child. Moreover, normal T and EBV‐B cells clear methylmalonate from the medium at a significant rate. Transduction of MCM‐deficient T cells with a recombinant retrovirus encoding the human MCM cDNA results in correction of propionate metabolism. These results establish the basis for developing haematopoietic cell‐based metabolic sink therapy for mut MMA by T lymphocyte/haematopoietic stem cell‐directed gene transfer.