Strong ubiquitous micro-promoters for recombinant adeno-associated viral vectors

Sunghee Chai; Leslie Wakefield; Mason Norgard; Bin Li; David Enicks; Daniel L. Marks; Markus Grompe

doi:10.1016/j.omtm.2023.05.013

Strong ubiquitous micro-promoters for recombinant adeno-associated viral vectors

Sunghee Chai, Leslie Wakefield, Mason Norgard, Bin Li, David Enicks, Daniel L. Marks, Markus Grompe

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

Significant progress has been made in developing recombinant adeno-associated virus (rAAV) for clinical gene therapy. While rAAV is a versatile gene delivery platform, its packaging limit of 4.7 kb limits the diseases it can target. Here, we report two unusually small promoters that enable the expression of larger transgenes than standard promoters. These micro-promoters are only 84 (MP-84) and 135 bp (MP-135) in size but have activity in most cells and tissues comparable to the CAG promoter, the strongest ubiquitous promoter to date. MP-84- and MP-135-based rAAV constructs displayed robust activity in cultured cells from the three different germ-layer lineages. In addition, reporter gene expression was documented in human primary hepatocytes and pancreatic islets and in multiple mouse tissues in vivo, including brain and skeletal muscle. MP-84 and MP-135 will enable the therapeutic expression of transgenes currently too large for rAAV vectors.

Original language	English (US)
Pages (from-to)	504-512
Number of pages	9
Journal	Molecular Therapy Methods and Clinical Development
Volume	29
DOIs	https://doi.org/10.1016/j.omtm.2023.05.013
State	Published - Jun 8 2023

Keywords

AAV packaging
adeno-associated virus
gene therapy
inverted terminal repeat
micro-promoter
universal promoter

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics

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10.1016/j.omtm.2023.05.013

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title = "Strong ubiquitous micro-promoters for recombinant adeno-associated viral vectors",

abstract = "Significant progress has been made in developing recombinant adeno-associated virus (rAAV) for clinical gene therapy. While rAAV is a versatile gene delivery platform, its packaging limit of 4.7 kb limits the diseases it can target. Here, we report two unusually small promoters that enable the expression of larger transgenes than standard promoters. These micro-promoters are only 84 (MP-84) and 135 bp (MP-135) in size but have activity in most cells and tissues comparable to the CAG promoter, the strongest ubiquitous promoter to date. MP-84- and MP-135-based rAAV constructs displayed robust activity in cultured cells from the three different germ-layer lineages. In addition, reporter gene expression was documented in human primary hepatocytes and pancreatic islets and in multiple mouse tissues in vivo, including brain and skeletal muscle. MP-84 and MP-135 will enable the therapeutic expression of transgenes currently too large for rAAV vectors.",

keywords = "AAV packaging, adeno-associated virus, gene therapy, inverted terminal repeat, micro-promoter, universal promoter",

author = "Sunghee Chai and Leslie Wakefield and Mason Norgard and Bin Li and David Enicks and Marks, {Daniel L.} and Markus Grompe",

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doi = "10.1016/j.omtm.2023.05.013",

language = "English (US)",

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T1 - Strong ubiquitous micro-promoters for recombinant adeno-associated viral vectors

AU - Chai, Sunghee

AU - Wakefield, Leslie

AU - Norgard, Mason

AU - Li, Bin

AU - Enicks, David

AU - Marks, Daniel L.

AU - Grompe, Markus

PY - 2023/6/8

Y1 - 2023/6/8

N2 - Significant progress has been made in developing recombinant adeno-associated virus (rAAV) for clinical gene therapy. While rAAV is a versatile gene delivery platform, its packaging limit of 4.7 kb limits the diseases it can target. Here, we report two unusually small promoters that enable the expression of larger transgenes than standard promoters. These micro-promoters are only 84 (MP-84) and 135 bp (MP-135) in size but have activity in most cells and tissues comparable to the CAG promoter, the strongest ubiquitous promoter to date. MP-84- and MP-135-based rAAV constructs displayed robust activity in cultured cells from the three different germ-layer lineages. In addition, reporter gene expression was documented in human primary hepatocytes and pancreatic islets and in multiple mouse tissues in vivo, including brain and skeletal muscle. MP-84 and MP-135 will enable the therapeutic expression of transgenes currently too large for rAAV vectors.

AB - Significant progress has been made in developing recombinant adeno-associated virus (rAAV) for clinical gene therapy. While rAAV is a versatile gene delivery platform, its packaging limit of 4.7 kb limits the diseases it can target. Here, we report two unusually small promoters that enable the expression of larger transgenes than standard promoters. These micro-promoters are only 84 (MP-84) and 135 bp (MP-135) in size but have activity in most cells and tissues comparable to the CAG promoter, the strongest ubiquitous promoter to date. MP-84- and MP-135-based rAAV constructs displayed robust activity in cultured cells from the three different germ-layer lineages. In addition, reporter gene expression was documented in human primary hepatocytes and pancreatic islets and in multiple mouse tissues in vivo, including brain and skeletal muscle. MP-84 and MP-135 will enable the therapeutic expression of transgenes currently too large for rAAV vectors.

KW - AAV packaging

KW - adeno-associated virus

KW - gene therapy

KW - inverted terminal repeat

KW - micro-promoter

KW - universal promoter

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DO - 10.1016/j.omtm.2023.05.013

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SN - 2329-0501

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EP - 512

JO - Molecular Therapy Methods and Clinical Development

JF - Molecular Therapy Methods and Clinical Development

ER -

Strong ubiquitous micro-promoters for recombinant adeno-associated viral vectors

Abstract

Keywords

ASJC Scopus subject areas

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