Improvement in survival and muscle function in an mdx/utrn-/- double mutant mouse using a human retinal dystrophin transgene

Roger Gaedigk, Douglas J. Law, Kathleen M. Fitzgerald-Gustafson, Steven G. McNulty, Ndona N. Nsumu, Ann C. Modrcin, Robert J. Rinaldi, David Pinson, Stephen C. Fowler, Mehmet Bilgen, Joanne Burns, Stephen D. Hauschka, Robert A. White

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Duchenne muscular dystrophy is a progressive muscle disease characterized by increasing muscle weakness and death by the third decade. mdx mice exhibit the underlying muscle disease but appear physically normal with ordinary lifespans, possibly due to compensatory expression of utrophin. In contrast, double mutant mice (mdx/utrn-/-), deficient for both dystrophin and utrophin die by ∼3 months and suffer from severe muscle weakness, growth retardation, and severe spinal curvature. The capacity of human retinal dystrophin (Dp260) to compensate for the missing 427 kDa muscle dystrophin was tested in mdx/utrn-/- mice. Functional outcomes were assessed by histology, EMG, MRI, mobility, weight and longevity. MCK-driven transgenic expression of Dp260 in mdx/utrn-/- mice converts their disease course from a severe, lethal muscular dystrophy to a viable, mild myopathic phenotype. This finding is relevant to the design of exon-skipping therapeutic strategies since Dp260 lacks dystrophin exons 1-29.

Original languageEnglish (US)
Pages (from-to)192-203
Number of pages12
JournalNeuromuscular Disorders
Volume16
Issue number3
DOIs
StatePublished - Mar 1 2006

Fingerprint

Inbred mdx Mouse
Dystrophin
Transgenes
Utrophin
Muscles
Survival
Muscle Weakness
Exons
Spinal Curvatures
Duchenne Muscular Dystrophy
Muscular Dystrophies
Histology
Phenotype
Weights and Measures
Growth

Keywords

  • Double mutant mouse
  • Dystrophin transgene
  • Muscle function

ASJC Scopus subject areas

  • Clinical Neurology
  • Pediatrics, Perinatology, and Child Health
  • Developmental Neuroscience
  • Neurology

Cite this

Gaedigk, R., Law, D. J., Fitzgerald-Gustafson, K. M., McNulty, S. G., Nsumu, N. N., Modrcin, A. C., ... White, R. A. (2006). Improvement in survival and muscle function in an mdx/utrn-/- double mutant mouse using a human retinal dystrophin transgene. Neuromuscular Disorders, 16(3), 192-203. https://doi.org/10.1016/j.nmd.2005.12.007

Improvement in survival and muscle function in an mdx/utrn-/- double mutant mouse using a human retinal dystrophin transgene. / Gaedigk, Roger; Law, Douglas J.; Fitzgerald-Gustafson, Kathleen M.; McNulty, Steven G.; Nsumu, Ndona N.; Modrcin, Ann C.; Rinaldi, Robert J.; Pinson, David; Fowler, Stephen C.; Bilgen, Mehmet; Burns, Joanne; Hauschka, Stephen D.; White, Robert A.

In: Neuromuscular Disorders, Vol. 16, No. 3, 01.03.2006, p. 192-203.

Research output: Contribution to journalArticle

Gaedigk, R, Law, DJ, Fitzgerald-Gustafson, KM, McNulty, SG, Nsumu, NN, Modrcin, AC, Rinaldi, RJ, Pinson, D, Fowler, SC, Bilgen, M, Burns, J, Hauschka, SD & White, RA 2006, 'Improvement in survival and muscle function in an mdx/utrn-/- double mutant mouse using a human retinal dystrophin transgene', Neuromuscular Disorders, vol. 16, no. 3, pp. 192-203. https://doi.org/10.1016/j.nmd.2005.12.007
Gaedigk, Roger ; Law, Douglas J. ; Fitzgerald-Gustafson, Kathleen M. ; McNulty, Steven G. ; Nsumu, Ndona N. ; Modrcin, Ann C. ; Rinaldi, Robert J. ; Pinson, David ; Fowler, Stephen C. ; Bilgen, Mehmet ; Burns, Joanne ; Hauschka, Stephen D. ; White, Robert A. / Improvement in survival and muscle function in an mdx/utrn-/- double mutant mouse using a human retinal dystrophin transgene. In: Neuromuscular Disorders. 2006 ; Vol. 16, No. 3. pp. 192-203.
@article{8ac9172406dd4e5ebde983b8029ebd7e,
title = "Improvement in survival and muscle function in an mdx/utrn-/- double mutant mouse using a human retinal dystrophin transgene",
abstract = "Duchenne muscular dystrophy is a progressive muscle disease characterized by increasing muscle weakness and death by the third decade. mdx mice exhibit the underlying muscle disease but appear physically normal with ordinary lifespans, possibly due to compensatory expression of utrophin. In contrast, double mutant mice (mdx/utrn-/-), deficient for both dystrophin and utrophin die by ∼3 months and suffer from severe muscle weakness, growth retardation, and severe spinal curvature. The capacity of human retinal dystrophin (Dp260) to compensate for the missing 427 kDa muscle dystrophin was tested in mdx/utrn-/- mice. Functional outcomes were assessed by histology, EMG, MRI, mobility, weight and longevity. MCK-driven transgenic expression of Dp260 in mdx/utrn-/- mice converts their disease course from a severe, lethal muscular dystrophy to a viable, mild myopathic phenotype. This finding is relevant to the design of exon-skipping therapeutic strategies since Dp260 lacks dystrophin exons 1-29.",
keywords = "Double mutant mouse, Dystrophin transgene, Muscle function",
author = "Roger Gaedigk and Law, {Douglas J.} and Fitzgerald-Gustafson, {Kathleen M.} and McNulty, {Steven G.} and Nsumu, {Ndona N.} and Modrcin, {Ann C.} and Rinaldi, {Robert J.} and David Pinson and Fowler, {Stephen C.} and Mehmet Bilgen and Joanne Burns and Hauschka, {Stephen D.} and White, {Robert A.}",
year = "2006",
month = "3",
day = "1",
doi = "10.1016/j.nmd.2005.12.007",
language = "English (US)",
volume = "16",
pages = "192--203",
journal = "Neuromuscular Disorders",
issn = "0960-8966",
publisher = "Elsevier Limited",
number = "3",

}

TY - JOUR

T1 - Improvement in survival and muscle function in an mdx/utrn-/- double mutant mouse using a human retinal dystrophin transgene

AU - Gaedigk, Roger

AU - Law, Douglas J.

AU - Fitzgerald-Gustafson, Kathleen M.

AU - McNulty, Steven G.

AU - Nsumu, Ndona N.

AU - Modrcin, Ann C.

AU - Rinaldi, Robert J.

AU - Pinson, David

AU - Fowler, Stephen C.

AU - Bilgen, Mehmet

AU - Burns, Joanne

AU - Hauschka, Stephen D.

AU - White, Robert A.

PY - 2006/3/1

Y1 - 2006/3/1

N2 - Duchenne muscular dystrophy is a progressive muscle disease characterized by increasing muscle weakness and death by the third decade. mdx mice exhibit the underlying muscle disease but appear physically normal with ordinary lifespans, possibly due to compensatory expression of utrophin. In contrast, double mutant mice (mdx/utrn-/-), deficient for both dystrophin and utrophin die by ∼3 months and suffer from severe muscle weakness, growth retardation, and severe spinal curvature. The capacity of human retinal dystrophin (Dp260) to compensate for the missing 427 kDa muscle dystrophin was tested in mdx/utrn-/- mice. Functional outcomes were assessed by histology, EMG, MRI, mobility, weight and longevity. MCK-driven transgenic expression of Dp260 in mdx/utrn-/- mice converts their disease course from a severe, lethal muscular dystrophy to a viable, mild myopathic phenotype. This finding is relevant to the design of exon-skipping therapeutic strategies since Dp260 lacks dystrophin exons 1-29.

AB - Duchenne muscular dystrophy is a progressive muscle disease characterized by increasing muscle weakness and death by the third decade. mdx mice exhibit the underlying muscle disease but appear physically normal with ordinary lifespans, possibly due to compensatory expression of utrophin. In contrast, double mutant mice (mdx/utrn-/-), deficient for both dystrophin and utrophin die by ∼3 months and suffer from severe muscle weakness, growth retardation, and severe spinal curvature. The capacity of human retinal dystrophin (Dp260) to compensate for the missing 427 kDa muscle dystrophin was tested in mdx/utrn-/- mice. Functional outcomes were assessed by histology, EMG, MRI, mobility, weight and longevity. MCK-driven transgenic expression of Dp260 in mdx/utrn-/- mice converts their disease course from a severe, lethal muscular dystrophy to a viable, mild myopathic phenotype. This finding is relevant to the design of exon-skipping therapeutic strategies since Dp260 lacks dystrophin exons 1-29.

KW - Double mutant mouse

KW - Dystrophin transgene

KW - Muscle function

UR - http://www.scopus.com/inward/record.url?scp=33644970593&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33644970593&partnerID=8YFLogxK

U2 - 10.1016/j.nmd.2005.12.007

DO - 10.1016/j.nmd.2005.12.007

M3 - Article

C2 - 16487708

AN - SCOPUS:33644970593

VL - 16

SP - 192

EP - 203

JO - Neuromuscular Disorders

JF - Neuromuscular Disorders

SN - 0960-8966

IS - 3

ER -