Optimizing promoters for recombinant adeno-associated virus-mediated gene expression in the peripheral and central nervous system using self-complementary vectors

Steven J. Gray, Stacey B. Foti, Joel W. Schwartz, Lavanya Bachaboina, Bonnie Taylor-Blake, Jennifer Coleman, Michael D. Ehlers, Mark J. Zylka, Thomas J. McCown, R. Jude Samulski

Research output: Contribution to journalArticle

126 Citations (Scopus)

Abstract

With the increased use of small self-complementary adeno-associated viral (AAV) vectors, the design of compact promoters becomes critical for packaging and expressing larger transgenes under ubiquitous or cell-specific control. In a comparative study of commonly used 800-bp cytomegalovirus (CMV) and chicken β-actin (CBA) promoters, we report significant differences in the patterns of cell-specific gene expression in the central and peripheral nervous systems. The CMV promoter provides high initial neural expression that diminishes over time. The CBA promoter displayed mostly ubiquitous and high neural expression, but substantially lower expression in motor neurons (MNs). We report the creation of a novel hybrid form of the CBA promoter (CBh) that provides robust long-term expression in all cells observed with CMV or CBA, including MNs. To develop a short neuronal promoter to package larger transgenes into AAV vectors, we also found that a 229-bp fragment of the mouse methyl-CpG-binding protein-2 (MeCP2) promoter was able to drive neuron-specific expression within the CNS. Thus the 800-bp CBh promoter provides strong, long-term, and ubiquitous CNS expression whereas the MeCP2 promoter allows an extra 570-bp packaging capacity, with low and mostly neuronal expression within the CNS, similar to the MeCP2 transcription factor.

Original languageEnglish (US)
Pages (from-to)1143-1153
Number of pages11
JournalHuman Gene Therapy
Volume22
Issue number9
DOIs
StatePublished - Sep 1 2011

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Dependovirus
Peripheral Nervous System
Methyl-CpG-Binding Protein 2
Cytomegalovirus
Central Nervous System
Motor Neurons
Product Packaging
Transgenes
Gene Expression
Actins
Chickens
Transcription Factors
Neurons

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Optimizing promoters for recombinant adeno-associated virus-mediated gene expression in the peripheral and central nervous system using self-complementary vectors. / Gray, Steven J.; Foti, Stacey B.; Schwartz, Joel W.; Bachaboina, Lavanya; Taylor-Blake, Bonnie; Coleman, Jennifer; Ehlers, Michael D.; Zylka, Mark J.; McCown, Thomas J.; Samulski, R. Jude.

In: Human Gene Therapy, Vol. 22, No. 9, 01.09.2011, p. 1143-1153.

Research output: Contribution to journalArticle

Gray, SJ, Foti, SB, Schwartz, JW, Bachaboina, L, Taylor-Blake, B, Coleman, J, Ehlers, MD, Zylka, MJ, McCown, TJ & Samulski, RJ 2011, 'Optimizing promoters for recombinant adeno-associated virus-mediated gene expression in the peripheral and central nervous system using self-complementary vectors', Human Gene Therapy, vol. 22, no. 9, pp. 1143-1153. https://doi.org/10.1089/hum.2010.245
Gray, Steven J. ; Foti, Stacey B. ; Schwartz, Joel W. ; Bachaboina, Lavanya ; Taylor-Blake, Bonnie ; Coleman, Jennifer ; Ehlers, Michael D. ; Zylka, Mark J. ; McCown, Thomas J. ; Samulski, R. Jude. / Optimizing promoters for recombinant adeno-associated virus-mediated gene expression in the peripheral and central nervous system using self-complementary vectors. In: Human Gene Therapy. 2011 ; Vol. 22, No. 9. pp. 1143-1153.
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