Correction of brain oligodendrocytes by AAVrh.10 intracerebral gene therapy in metachromatic leukodystrophy mice

Françoise Piguet, Dolan Sondhi, Monique Piraud, Françoise Fouquet, Neil R. Hackett, Ornella Ahouansou, Marie Thérèse Vanier, Ivan Bieche, Patrick Aubourg, Ronald Crystal, Nathalie Cartier, Caroline Sevin

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder characterized by accumulation of sulfatides in glial cells and neurons, the result of an inherited deficiency of arylsulfatase A (ARSA; EC 3.1.6.8) and myelin degeneration in the central and peripheral nervous systems. No effective treatment is currently available for the most frequent late infantile (LI) form of MLD, which results in rapid neurological degradation and early death after the onset of clinical manifestations. To potentially arrest or reverse disease progression, ARSA enzyme must be rapidly delivered to brain oligodendrocytes of patients with LI MLD. We previously showed that brain gene therapy with adeno-associated virus serotype 5 (AAV5) driving the expression of human ARSA cDNA under the control of the murine phosphoglycerate kinase (PGK) promoter alleviated most long-term disease manifestations in MLD mice. Herein, we evaluated the short-term effects of AAVrh.10 driving the expression of human ARSA cDNA under the control of the cytomegalovirus/β-actin hybrid (CAG/cu) promoter in 8-month-old MLD mice that already show marked sulfatide accumulation and brain pathology. Within 2 months, and in contrast to results with the AAV5-PGK-ARSA vector, a single intrastriatal injection of AAVrh.10cuARSA resulted in correction of brain sulfatide storage, accumulation of specific sulfatide species in oligodendrocytes, and associated brain pathology in the injected hemisphere. Better potency of the AAVrh.10cuARSA vector was mediated by higher neuronal and oligodendrocyte transduction, axonal transport of the AAVrh.10 vector and ARSA enzyme, as well as higher CAG/cu promoter driven expression of ARSA enzyme. These results strongly support the use of AAVrh.10cuARSA vector for intracerebral gene therapy in rapidly progressing early-onset forms of MLD.

Original languageEnglish
Pages (from-to)903-914
Number of pages12
JournalHuman Gene Therapy
Volume23
Issue number8
DOIs
Publication statusPublished - 1 Aug 2012
Externally publishedYes

Fingerprint

Metachromatic Leukodystrophy
Oligodendroglia
Genetic Therapy
Sulfoglycosphingolipids
Brain
Phosphoglycerate Kinase
Dependovirus
Enzymes
Complementary DNA
Cerebroside-Sulfatase
Pathology
Axonal Transport
Peripheral Nervous System
Myelin Sheath
Cytomegalovirus
Neuroglia
Disease Progression
Actins
Central Nervous System
Neurons

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Piguet, F., Sondhi, D., Piraud, M., Fouquet, F., Hackett, N. R., Ahouansou, O., ... Sevin, C. (2012). Correction of brain oligodendrocytes by AAVrh.10 intracerebral gene therapy in metachromatic leukodystrophy mice. Human Gene Therapy, 23(8), 903-914. https://doi.org/10.1089/hum.2012.015

Correction of brain oligodendrocytes by AAVrh.10 intracerebral gene therapy in metachromatic leukodystrophy mice. / Piguet, Françoise; Sondhi, Dolan; Piraud, Monique; Fouquet, Françoise; Hackett, Neil R.; Ahouansou, Ornella; Vanier, Marie Thérèse; Bieche, Ivan; Aubourg, Patrick; Crystal, Ronald; Cartier, Nathalie; Sevin, Caroline.

In: Human Gene Therapy, Vol. 23, No. 8, 01.08.2012, p. 903-914.

Research output: Contribution to journalArticle

Piguet, F, Sondhi, D, Piraud, M, Fouquet, F, Hackett, NR, Ahouansou, O, Vanier, MT, Bieche, I, Aubourg, P, Crystal, R, Cartier, N & Sevin, C 2012, 'Correction of brain oligodendrocytes by AAVrh.10 intracerebral gene therapy in metachromatic leukodystrophy mice', Human Gene Therapy, vol. 23, no. 8, pp. 903-914. https://doi.org/10.1089/hum.2012.015
Piguet, Françoise ; Sondhi, Dolan ; Piraud, Monique ; Fouquet, Françoise ; Hackett, Neil R. ; Ahouansou, Ornella ; Vanier, Marie Thérèse ; Bieche, Ivan ; Aubourg, Patrick ; Crystal, Ronald ; Cartier, Nathalie ; Sevin, Caroline. / Correction of brain oligodendrocytes by AAVrh.10 intracerebral gene therapy in metachromatic leukodystrophy mice. In: Human Gene Therapy. 2012 ; Vol. 23, No. 8. pp. 903-914.
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