Dystrophin production induced by myoblast transfer therapy in Duchenne muscular dystrophy

Law, Peter K.; Bertorini, Tulio E.; Goodwin, Tena G.; Chen, Ming; Fang, Qiuwen; Li, Hua Ju; Kirby, Dana S.; Florendo, J. Ann; Herrod, Henry G.; Golden, Gerald S.

doi:10.1016/0140-6736(90)91628-n

Cited by 124 publications

(47 citation statements)

References 4 publications

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“…Stable muscle expression of reporter genes up to 60 days has also been reported by Wolff et al (6) following direct injection of plasmid DNA. It is difficult to compare our results with myoblast transplantation, where the presence of donor proteins was ascertained up to 99 days in the mdx mouse (5) and 92 days in a single DMD patient (who was also under parallel cyclosporin treatment) (22). In the most successful experiments in mdx mouse, 10-30% offibers were dystrophin positive.…”

Section: Discussionmentioning

confidence: 89%

Adenovirus as an expression vector in muscle cells in vivo.

Quantin

Perricaudet

Tajbakhsh

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

276

115

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Attempting gene transfer in muscle raises difficult problems: the nuclei of mature muscle fibers do not undergo division, thus excluding strategies involving replicative integration of exogenous DNA. As adenovirus has been reported to be an efficient vector for the transfer of an enzyme encoding gene in mice, we decided to explore its potential for muscle cells. Advantages of adenovirus vectors are their independence of host cell replication, broad host range, and potential capacity for large foreign DNA inserts. We constructed a recombinant adenovirus containing the fi-galactosidase reporter gene under the control of muscle-specific regulatory sequences. This recombinant virus was able to direct expression of the 3-galactosidase in myotubes in vitro. We report its in vivo expression in mouse muscles up to 75 days after infection. The efficiency and stability of expression we obtained compare very favorably with other strategies proposed for gene or myoblast transfer in muscle in vivo.The eventual correction of muscle diseases, and especially Duchenne muscular dystrophy (DMD), raises very difficult problems. As much as 50% ofDMD cases are sporadic (1) and thus cannot be prevented by current genetic counseling and prenatal diagnosis approaches; this frequency is even higher in mitochondrial myopathies (2). It is thus necessary to actively explore therapeutic strategies. The main problems to overcome are the large number of muscles to be treated and the nondividing nature of mature muscle cells. Moreover, the size of the sequences coding for dystrophin [11,056 base pairs (bp)] is incompatible with most vectors used for gene transfer; in addition, dystrophin is an intracellular protein thought to have a structural role in the muscle cells, whereas most of the current gene therapy approaches concern circulating proteins such as a1-antitrypsin (3), or diseases due to an enzymatic defect, where a very partial restoration of the activity might be sufficient, such as adenosine deaminase (4).Two strategies have been proposed to date: myoblast transplantation (5) and direct DNA injection (6). We decided to explore a third route using adenovirus as a vector for gene expression in muscle cells. Such a vector has already been used to correct postnatally an ornithine transcarbamoylase deficiency in mouse (7,8) 2581The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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Section: Discussionmentioning

confidence: 89%

Adenovirus as an expression vector in muscle cells in vivo.

Quantin

Perricaudet

Tajbakhsh

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

276

115

View full text Add to dashboard Cite

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“…14,15 Despite positive results in these small rodents, [16][17][18][19][20] clinical trials have presented limited success. [21][22][23][24][25][26][27][28][29] Improvements of injection and immunosuppression parameters have recently been achieved in primates 9,10,30 and translated to the human situation with encouraging, although localized success. 31 Nevertheless, one of the most important problems of heterologous MT remains the immune response raised by the recipient against donor cells.…”

Section: Introductionmentioning

confidence: 99%

Normal growth and regenerating ability of myoblasts from unaffected muscles of facioscapulohumeral muscular dystrophy patients

Vilquin

Sacconi

et al. 2005

Gene Ther

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Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease characterized by a typical regional distribution, featuring composed patterns of clinically affected and unaffected muscles. No treatment is available for this condition, in which the pathophysiological mechanism is still unknown. Autologous transfer of myoblasts from unaffected to affected territories could be considered as a potential strategy to delay or stop muscle degeneration. To evaluate the feasibility of this concept, we explored and compared the growth and differentiation characteristics of myoblasts prepared from phenotypically unaffected muscles of five FSHD patients and 10 control donors. According to a clinically approved procedure, 10 9 cells of a high degree of purity were obtained within 16-23 days. More than 80% of these cells were myoblasts, as demonstrated by labeling of the muscle markers CD56 and desmin. FSHD myoblasts presented a doubling time equivalent to that of control cells; they kept high proliferation ability and did not show early telomere shortening. In vitro, these cells were able to differentiate and to express muscle-specific antigens. In vivo, they participated to muscle structures when injected into immunodeficient mice. These data suggest that myoblasts expanded from unaffected FSHD muscles may be suitable tools in view of autologous cell transplantation clinical trials.

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“…This treatment regime, referred to as myoblast transfer therapy (MTT), depends upon: (i) the survival of cultured donor myoblasts; (ii) their migration away from the injection site; (iii) their fusion with one another, or host myofibers to form do nor-host hybrid fibers; and (iv) the ability of these hy brid myofibers to express normal dystrophin. MTT has been largely unsuccessful in both experimental and clin ical trials because most cultured donor myoblasts die soon after injection into host muscle (6,14,28,29,(33)(34)(35)37,39,43,44,66). This is the case even when fully histocompatible donor-host combinations are used (14,34).…”

Section: Introductionmentioning

confidence: 99%

Exposure to Tissue Culture Conditions Can Adversely Affect Myoblast Behavior in Vivo in Whole Muscle Grafts: Implications for Myoblast Transfer Therapy

Smythe

Grounds

2000

Cell Transplant

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The effects of tissue culture conditions on the viability of myoblasts in whole muscles transplanted in vivo were investigated. Whole male (SJL/J) donor muscles were exposed to various tissue culture reagents and proteolytic enzymes, and allografted into female (SJL/J) host mice. Desmin immunohistochemistry was used to assess the numbers of myogenic cells (as an index of myoblast viability and the extent of regeneration) in tissue sections of whole-muscle grafts sampled on days 7 and 14. DNA quantitation with a Y-chromosome-specific probe was used to determine the total Y-l sequence DNA (as an index of myoblast survival and proliferation) in whole-muscle grafts sampled on days 1, 3, and 7. In grafts exposed to serum-free medium, there was a delay in myoblast fusion at 7 days that was recovered by 14 days, but exposure to serum (10% or 20%) had a prolonged adverse effect on myotube formation at 14 days. DNA quantitation demonstrated that either serum-free culture medium or 10% serum enhanced the number of male cells within whole-muscle grafts at 7 days. Proteolytic digestion (even for 5 min) of whole muscles prior to grafting was extremely detrimental to myoblast survival and viability at 7 and 14 days. The unexpected finding of adverse effects of tissue culture conditions on the regeneration of whole-muscle grafts in vivo appears to parallel the major problem of the rapid death of isolated cultured donor myoblasts after injection in myoblast transfer therapy. The use of whole-muscle grafts provides an alternative and sensitive model to analyze the crucial effects of various tissue culture components on the subsequent survival and proliferation of myogenic cells in vivo.

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Dystrophin production induced by myoblast transfer therapy in Duchenne muscular dystrophy

Cited by 124 publications

References 4 publications

Adenovirus as an expression vector in muscle cells in vivo.

Adenovirus as an expression vector in muscle cells in vivo.

Normal growth and regenerating ability of myoblasts from unaffected muscles of facioscapulohumeral muscular dystrophy patients

Exposure to Tissue Culture Conditions Can Adversely Affect Myoblast Behavior in Vivo in Whole Muscle Grafts: Implications for Myoblast Transfer Therapy

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