Abstract
Gene therapy as a treatment for neuromuscular diseases is an ever-developing concept based on the use of DNA as the therapeutic agent. In the search for appropriate strategies a bottleneck exists, however, concerning the targeting of vectors carrying the therapeutic gene, to all pathologic sites. These diseases are often characterised by multiple widespread lesions spread over a large area, rendering administration by local injection into tissues, clinically irrelevant. With this in mind, we have proposed that circulating cells (monocytes/macrophages), which home naturally to inflammatory lesions, characteristic of degenerating muscle, could be used as shuttles able to track down every damaged site, and deliver there a corrective gene. Our aim is to mobilise a corrective gene from these infiltrating monocyte-macrophages, into muscle cells, a process of in situ cell to cell gene transfer which could be accomplished using a retroviral vector, since the regeneration process involves the proliferation of muscle precursors before they fuse to form replacement fibres. For this, monocyte-macrophages must be engineered into ‘packaging cells’ containing both the replication deficient retrovirus carrying the gene of interest and an helper genome (gag-pol-env) needed for its assembly and secretion. Here, we have transduced a monocyte cell line using a defective murine Moloney leukemia retrovirus carrying the LacZ reporter gene. This provided us with a platform to investigate the possibility of gag-pol-env vector driven packaging of the defective retrovirus by macrophages. We show that an herpes simplex virus type I amplicon harbouring the Moloney gag, pol, env sequences is able to rescue the defective retrovirus vector from macrophages, allowing gene transfer into muscle precursor cells. After fusion, these cells gave rise to genetically modified myotubes in vitro.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Acsadi G, Dickson G, Love DR, Jani A, Walsh FS, Gurusinghe A, Wolff JA and Davies KE (1991) Human dystrophin expression in mdx mice after intramuscular injection of DNA constructs. Nature 352: 815-818.
Bilang-Bleuel A, Revah F, Colin P, Locquet I, Robert JJ, Mallet J and Horellou P (1997). Intrastriatal injection of an adenoviral vector expressing glial-cell-line-derived neurotrophic factor prevents dopaminergic neuron degeneration and behavioral impairment in a rat model of Parkinson disease. Proc Natl Acad Sci USA 94(16): 8818-8823.
Carlson BM (1986) Regeneration of entire squeletal muscle. Federation Proceedings 45(5): 1456-1460.
Crocker PR and Gordon SJ (1989) Mouse macrophage hemagglutinin (sheep erythrocyte receptor) with specificity for sialylated glycoconjugates characterized by a monoclonal antibody. Exp Med 169(4): 1332-1346.
Deconinck N, Ragot T, Marechal G, Perricaudet M and Gillis JM (1996) Functional protection of dystrophic mouse (mdx) muscles after adenovirus-mediated transfer of a dystrophin minigene. Proc Natl Acad Sci USA 93(8): 3570-3574.
Emery A, Duchenne Muscular Dystrophy, Oxford University Press, 1993.
Erbacher P, Bousser MT, Raimond J, Monsigny M, Midoux P and Roche AC (1996) Gene transfer by DNA/glycosylated polylysine complexes into human blood monocyte-derived macrophages. Hum Gene Ther 7(6): 721-729.
Fassati A, Wells DJ, Walsh FS and Dickson G (1996) Transplantation of retroviral producer cells for in vivo gene transfer into mouse skeletal muscle. H Gene Therapy 7(5): 595-602.
Fassati A, Wells DJ, Sgro Serpente PA, Walsh FS, Brown SC, Strong PN and Dickson G (1997) Genetic correction of dystrophin deficiency and skeletal muscle remodeling in adult MDX mouse via transplantation of retroviral producer cells. J Clin Invest 100(3): 620-628.
Fraefel C, Song S, Lim F, Lang P, Yu L, Wang Y, Wild P and Geller AI (1996) Helper virus-free transfer of herpes simplex virus type 1 plasmid vectors into neural cells. J Virol 70(10): 7190-7197.
Haddada H, Lopez M, Martinache C, Ragot T, Abina MA and Perricaudet M (1993) Efficient adenovirus-mediated gene transfer into human blood monocyte-derived macrophages. Biochem Biophys Res Commun 195(3): 1174-1183.
Huang S, Endo RI and Nemerow GR (1995) Upregulation of integrins alpha v beta 3 and alpha v beta 5 on human monocytes and T lymphocytes facilitates adenovirus-mediated gene delivery. J Virol 69(4): 2257-2263.
Jacoby DR, Fraefel C and Breakefield XO (1997) Hybrid vectors: a new generation of virus-based vectors designed to control the cellular fate of delivered genes. Gene Therapy 4(12): 1281-1283.
Kristoffersen AK, Sindre H, Mandi Y, Rollag H and Degre M (1997) Effect of adenovirus 2 on cellular gene activation in blood-derived monocytes and macrophages. APMIS 105(5): 402-409.
Lawrence MS, Ho DY, Sun GH, Steinberg GK and Sapolsky RM (1996) Overexpression of Bcl-2 with herpes simplex virus vectors protects CNS neurons against neurological insults in vitro and in vivo. J Neurosci 16(2): 486-496.
Le Gal La Salle G, Robert JJ, Berrard S, Ridoux V, Stratford-Perricaudet LD, Perricaudet M and Mallet J (1993) An adenovirus vector for gene transfer into neurons and glia in the brain. Science 259(5097): 988-990.
Lowenstein PR, Fournel S, Bain D, Tomasec P, Clissold P, Castro MG and Epstein A (1994) Herpes simplex virus 1 (HSV-1) helper co-infection affects the distribution of an amplicon encoded protein in glia. Neuroreport 5(13): 1625-1630.
Miller AD and Rosman GJ (1989) Improved retroviral vectors for gene transfer and expression. BioTechniques 7(9): 980-982.
Naldini L, Blomer U, Gallay P, Ory D, Mulligan R, Gage FH, Verma IM and Trono D (1996) In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272(50259): 263-267.
Orimo S, Hiyamuta E, Arahata K and Sugita H (1991) Analysis of inflammatory cells and complement C3 in bupivacaine-induced myonecrosis. Muscle and Nerve 14(6): 515-520.
Parrish EP, Cifuentes-Diaz C, Li ZL, Vicart P, Paulin D, Dreyfus PA, Peschanski M, Harris AJ and Garcia L (1996) Targeting widespread sites of damage in dystrophic muscle: engrafted macrophages as potential shuttles. Gene Therapy 3(1): 13-20.
Peel AL, Zolotukhin S, Schrimsher GW, Muzyczka N and Reier PJ (1997) Efficient transduction of green fluorescent protein in spinal cord neurons using adeno-associated virus vectors containing cell type-specific promoters. Gene Therapy 4(1): 16-24.
Quantin B, Perricaudet LD, Tajbakhsh S and Mandel JL (1992) Adenovirus as an expression vector in muscle cells in vivo. Proc Natl Acad Sci USA 89(7): 2581-2584.
Ragot T, Vincent N, Chafey P, Vigne E, Gilgenkrantz H, Couton D, Cartaud J, Briand P, Kaplan JC, Perricaudet M. et al. (1993) Efficient adenovirus-mediated transfer of a human minidystrophin gene to skeletal muscle of mdx mice. Nature 361(60413): 647-650.
Savard N, Cosset FL and Epstein AL (1997) Defective herpes simplex virus type 1 vectors harboring gag, pol, and env genes can be used to rescue defective retrovirus vectors. J Virol 71(5): 4111-4117.
Schultz E and Lipton PH (1980) Mech Aging Dev 13: 105-112.
Smith MJ and Koch GLE (1987) Differential expression of murine macrophage surface glycoprotein antigens in intracellular membranes. J Cell Sci 87(Pt1): 113-119.
Snyder RO, Miao CH, Patijn GA, Spratt SK, Danos O, Nagy D, Gown AM, Winther B, Meuse L, Cohen LK, Thompson AR and Kay MA (1997) Persistent and therapeutic concentrations of human factor IX in mice after hepatic gene transfer of recombinant AAV vectors. Nat Genet 16(3): 270-276.
Snyder RO, Spratt SK, Lagarde C, Bohl D, Kaspar B, Sloan B, Cohen LK and Danos O (1997) Efficient and stable adeno-associated virus-mediated transduction in the skeletal muscle of adult immunocompetent mice. Hum Gene Ther 8(16): 1891-1900.
Spaete RR and Frenkel N (1982) The herpes simplex virus amplicon: a new eucaryotic defective-virus cloning-amplifying vector. Cell 30(1): 295-304.
Vicart P, Schwartz B, Vandewalle A, Bens M, Delouis C, Panthier JJ, Pournin S, Babinet C and Paulin D (1994) Immortalization of multiple cell types from transgenic mice using a transgene containing the vimentin promoter and a conditional oncogene. Exp Cell Res 214(1): 35-45.
Weir JP, Dacquel EJ and Aronovitz J (1996) Herpesvirus vector-mediated gene delivery to human monocytes. Hum Gene Ther 7(11): 1331-1338.
Vincent N, Ragot T, Gilgenkrantz H, Couton D, Chafey P, Gregoire A, Briand P, Kaplan JC, Kahn A and Perricaudet M (1993) Long-term correction of mouse dystrophic degeneration by adenovirus-mediated transfer of a minidystrophin gene. Nature Genet 5(2): 130-134.
Wickham TJ, Tzeng E, Shears LL 2nd, Roelvink PW, Li Y, Lee GM, Brough DE, Lizonova A and Kovesdi I (1997) Increased in vitro and in vivo gene transfer by adenovirus vectors containing chimeric fiber proteins. J Virol 71(11): 8221-8229.
Wolff JA, Malone RW, Williams P, Chong W, Acsadi G, Jani A and Felgner PL (1990) Direct gene transfer into mouse muscle in vivo. Science 245(4949): 1465-1468.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Parrish, E., Peltékian, E., Dickson, G. et al. Cell engineering for muscle gene therapy: Extemporaneous production of retroviral vector packaging macrophages using defective herpes simplex virus type 1 vectors harbouring gag, pol, env genes. Cytotechnology 30, 173–180 (1999). https://doi.org/10.1023/A:1008022713466
Issue Date:
DOI: https://doi.org/10.1023/A:1008022713466