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Blood, Vol. 94 No. 9 (November 1), 1999:
pp. 3193-3198
Reversal of Metabolic Block in Glycolysis by Enzyme Replacement in
Triosephosphate Isomerase-Deficient Cells
Art Ationu,
Ann Humphries,
Michel R.A. Lalloz,
Roopen Arya,
Barbara Wild,
Joanne Warrilow,
Jennifer Morgan,
Alastair J. Bellingham, and
D. Mark Layton
From the Department of Haematological Medicine, Guy's, King's, and
St Thomas' School of Medicine; and the Muscle Cell Biology Group,
Medical Research Council, Imperial College School of Medicine,
Hammersmith Hospital, London, UK.
Inherited deficiency of the housekeeping enzyme triosephosphate
isomerase (TPI) is the most severe clinical disorder of glycolysis. Homozygotes manifest congenital hemolytic anemia and progressive neuromuscular impairment, which in most cases pursues an inexorable course with fatal outcome in early childhood. No effective therapy is
available. Hitherto specific enzyme replacement has not been attempted
in disorders of glycolysis. Primary skeletal muscle myoblasts and
Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines
generated from homozygous TPI-deficient patients were cultured in the
presence of exogenous enzyme or cocultured with human K562
erythroleukemia cells as an exogenous source of TPI. Uptake of active
enzyme by TPI-deficient cells resulted in reversal of intracellular
substrate accumulation, with a reduction in dihydroxyacetone phosphate
(DHAP) concentration to levels seen in TPI-competent cells. Evidence of
successful metabolic correction of TPI deficiency in vitro establishes
the feasibility of enzyme replacement therapy, and has important
implications for the potential role of allogeneic bone marrow
transplantation and gene therapy as a means of sustained delivery of
functional enzyme in vivo.
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