title: Pleiotrophin gene therapy for peripheral ischemia: evaluation of full-length and truncated gene variants.
abstract: Pleiotrophin (PTN) is a growth factor with both pro-angiogenic and limited pro-tumorigenic activity. We evaluated the potential for PTN to be used for safe angiogenic gene therapy using the full length gene and a truncated gene variant lacking the domain implicated in tumorigenesis. Mouse myoblasts were transduced to express full length or truncated PTN (PTN or T-PTN), along with a LacZ reporter gene, and injected into mouse limb muscle and myocardium. In cultured myoblasts, PTN was expressed and secreted via the Golgi apparatus, but T-PTN was not properly secreted. Nonetheless, no evidence of uncontrolled growth was observed in cells expressing either form of PTN. PTN gene delivery to myocardium, and non-ischemic skeletal muscle, did not result in a detectable change in vascularity or function. In ischemic hindlimb at 14 days post-implantation, intramuscular injection with PTN-expressing myoblasts led to a significant increase in skin perfusion and muscle arteriole density. We conclude that (1) delivery of the full length PTN gene to muscle can be accomplished without tumorigenesis, (2) the truncated PTN gene may be difficult to use in a gene therapy context due to inefficient secretion, (3) PTN gene delivery leads to functional benefit in the mouse acute ischemic hindlimb model.
authors: Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, United States of America.
authors: Qizhi
authors: Q
authors: Fang
authors: Pamela Y
authors: PY
authors: Mok
authors: Anila E
authors: AE
authors: Thomas
authors: Daniel J
authors: DJ
authors: Haddad
authors: Shereen A
authors: SA
authors: Saini
authors: Brian T
authors: BT
authors: Clifford
authors: Neel K
authors: NK
authors: Kapasi
authors: Olivia M
authors: OM
authors: Danforth
authors: Minako
authors: M
authors: Usui
authors: Weisheng
authors: W
authors: Ye
authors: Emmy
authors: E
authors: Luu
authors: Rikki
authors: R
authors: Sharma
authors: Maya J
authors: MJ
authors: Bartel
authors: Jeremy A
authors: JA
authors: Pathmanabhan
authors: Andrew A S
authors: AA
authors: Ang
authors: Richard E
authors: RE
authors: Sievers
authors: Randall J
authors: RJ
authors: Lee
authors: Matthew L
authors: ML
authors: Springer
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000473:pathology; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D015316:Genetic Therapy; D006614:Hindlimb / Q000098:blood supply / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells / Q000502:physiology; D006801:Humans; D007511:Ischemia / Q000628:therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000473:pathology; D032446:Myoblasts / Q000378:metabolism / Q000637:transplantation; D009206:Myocardium / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000502:physiology; D018919:Neovascularization, Physiologic; D010446:Peptide Fragments / Q000235:genetics* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D010446:Peptide Fragments; C066845:pleiotrophin
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