Molecular therapy : the journal of the American Society of Gene Therapy
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We have previously demonstrated safety of G207, a doubly mutated (deletion of both gamma(1)34.5 loci, insertional inactivation of U(L)39) herpes simplex virus (HSV) for patients stereotactically inoculated in enhancing portions of recurrent malignant gliomas. We have now determined safety of two inoculations of G207, before and after tumor resection. Inclusion criteria were histologically proven recurrent malignant glioma, Karnofsky score >or=70, and ability to resect the tumor without ventricular system breach. ⋯ Radiographic and neuropathologic evidence suggestive of antitumor activity is reported. Evidence of viral replication was demonstrated. G207 appears safe for multiple dose delivery, including direct inoculation into the brain surrounding tumor resection cavity.
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The herpes simplex virus-1 (HSV-1)-infected cell protein 0 (ICP0) is an E3 ubiquitin ligase implicated in cell cycle arrest and DNA repair inhibition. Convection-enhanced delivery (CED) of either the replication-defective, ICP0-producing HSV-1 mutant, d106, or the recombinant d109, devoid of all viral genome expression, was performed to determine the in vivo efficacy of ICP0 in combination with ionizing radiation (IR) or systemic temozolomide (TMZ) in the treatment of glioblastoma multiforme (GBM). ⋯ Median survival for animals that underwent treatment with HBSS alone, d109 alone, d106 alone, HBSS + IR, HBSS + TMZ, d109 + IR, d106 + IR, and d106 + TMZ was 28, 35, 41, 39, 44, 39, 68 (P < 0.01), and 66 days (P < 0.01), respectively. Intracerebral d106 CED resulted in a significant increase in athymic nude mouse survival when combined with IR or TMZ. d106 CED allows for distribution of HSV-1 in human GBM xenografts and persistent viral infection.
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Intranasal HGF administration ameliorates the physiologic and morphologic changes in lung emphysema.
Hepatocyte growth factor (HGF) has multiple biological effects on stem cells, epithelial proliferation, and wound healing. In this study, we investigated a possible therapeutic benefit of intranasal HGF on elastase-induced emphysema, and assessed the role of stem/progenitor cells in this process. HGF was given twice a week for 1-4 weeks after the establishment of emphysema in mice. ⋯ Further, HGF increased the expression levels of proliferating cell nuclear antigen (PCNA) and cytokeratin-19. Also, their immunohistochemical staining patterns were colocalized, indicative of epithelial multiplication. The results of the study show that intranasal treatment with HGF reverses both the physiological and morphometric changes of lung emphysema, possibly through stem-cell mobilization and alveolar regeneration, providing a nonsurgical treatment and suggesting the possibility of achieving a similar effect in humans.
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A combination treatment of AAV2-hAADC with oral levodopa is a novel therapeutic approach that is being developed for late-stage Parkinson's disease. Biodistribution of AAV2-hAADC was assessed over a wide range of vector dose in 12 monkeys with parkinsonian syndrome, 6 months after intraputamenal infusion. Quantitative PCR (Q-PCR) from all the major neuroanatomical regions of the brain indicated a dose-dependent increase in vector DNA, with 99% being detected in the target site and other basal ganglia tissues. ⋯ Outside of the brain, trace amounts of vector DNA were detected in the spleens of animals in the two highest dose groups, but not in any other peripheral tissue, blood, or cerebrospinal fluid. Some increase in neutralizing antibody titers to adeno-associated virus type-2 (AAV2) capsid protein was observed in monkeys that received high doses of AAV2-hAADC or control AAV2-GFP. This study further validates convection-enhanced delivery (CED) as the preferred method of viral vector delivery to the brain, and supports a Phase I clinical testing of AAV2-hAADC in humans with Parkinson's disease.
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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder arising from the selective death of motor neurons. Approximately 20% of familial ALS (fALS) cases are caused by toxic gain-of-function mutations in the superoxide dismutase 1 (SOD1) gene. We as well as others have provided proof-of-principle for the use of RNA interference (RNAi) against mutant SOD1 as a potential therapy for fALS. ⋯ SOD1 protein levels were reduced by >50% in all the muscles that were examined. Crucially, this silencing profile did not alter the course of the disease in this fALS model, thereby providing compelling evidence that SOD1-mediated damage within skeletal muscles does not contribute to death of motor neurons in ALS. Further, this study demonstrates that motor neurons can be transduced across the length of the spinal cord through a single noninvasive delivery of rAAV.