Overexpression of Human Methylmalonyl CoA Mutase in Mice after In Vivo Gene Transfer with Asialoglycoprotein/Polylysine/DNA Complexes

Jozsef Stankovics, Ana Maria Crane, Elizabeth Andrews, Catherine H. wu, George Y. wu, Fred D. Ledley

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

Abstract

Methylmalonic acidemia resulting from genetic deficiency of methylmalonyl CoA mutase (MCM) is an often fatal metabolic disease. Somatic gene therapy for this disorder may require gene replacement in the liver. We describe overexpression of MCM in the liver of mice after in vivo gene delivery using asialoglycoprotein/polylysine/DNA (ASO/PL/DNA) targeted delivery to the liver of plasmids expressing recombinant MCM. After intravenous administration of the ASO/PL/DNA complex, the vector sequences are cleared from the blood with t 1/2 = 2.5 min and >95% of the vector is taken up by the liver. Vector sequences are cleared from the liver with t 1/2 = 1.0–1.3 hr. MCM enzyme activity in the liver increases to levels 30–40% over baseline 6–24 hr after injection. No acute or chronic toxicity was observed. This net level of expression is likely to be therapeutic for MCM if the complex could be administered repetitively to treat acute episodes of life-threatening acidosis or establish a steady-state level of MCM activity. Repetitive administration of the ASO/PL/DNA complexes in mice was associated with formation of antibodies against asialo-orosomucoid and the asialo-orosomucoid complex but not against DNA.

Original languageEnglish (US)
Pages (from-to)1095-1104
Number of pages10
JournalHuman Gene Therapy
Volume5
Issue number9
DOIs
StatePublished - Sep 1 1994

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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