Ectopic matrix metalloproteinase-9 expression in human brain tumor cells enhances oncolytic HSV vector infection

• Published in: Gene therapy Vol. 17; no. 10; pp. 1200 - 1205
• Main Authors: Hong, C-S, Fellows, W, Niranjan, A, Alber, S, Watkins, S, Cohen, J B, Glorioso, J C, Grandi, P
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2010; Nature Publishing Group
• Subjects: 631/250/255/2514; 631/326/596/2561; 631/67/1922; 631/80/84/750; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Applied cell therapy and gene therapy; Basement membranes; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Biotechnology; Brain cancer; Brain Neoplasms - enzymology; Brain Neoplasms - therapy; Brain tumors; Care and treatment; Cell Biology; Cell Line, Tumor; Cell migration; Cell Movement; Collagen (type IV); Development and progression; enabling-technologies; Expression vectors; Extracellular matrix; Extracellular Matrix - metabolism; Female; Fundamental and applied biological sciences. Psychology; Gelatinase B; Gene Expression; Gene Expression Regulation, Enzymologic; Gene Therapy; Genetic aspects; Genetic Therapy - methods; Genetic Vectors - genetics; Health aspects; Health. Pharmaceutical industry; Herpes simplex; Herpes simplex virus; Herpes viruses; Human Genetics; Humans; Industrial applications and implications. Economical aspects; Infections; Matrix metalloproteinase; Matrix Metalloproteinase 9 - genetics; Medical sciences; Metalloenzymes; Metalloproteinase; Mice; Mice, Inbred BALB C; Mice, Nude; Nanotechnology; Neoplasm Transplantation; Neuroblastoma; Neuroblastoma cells; Oncolysis; Oncolytic Virotherapy - methods; Oncolytic Viruses - genetics; Physiological aspects; Proteases; Simplexvirus - genetics; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Tumor cells; Tumors; Virions; Xenografts; United States; brain tumor; HSV; MMP-9; ECM; oncolysis; Human; Nervous system diseases; Enzyme; Metalloendopeptidases; Intracranial tumor; Gelatinase B; Cerebral disorder; Infection; Peptidases; Central nervous system disease; Oncolysis; Hydrolases; Ectopia; Gene therapy; Vector; Tumor cell
• ISSN: 0969-7128; 1476-5462
• DOI: 10.1038/gt.2010.66

Oncolytic herpes simplex virus (oHSV) vectors have shown promise in the treatment of patients with recurrent brain tumors although few complete responses have accrued. Impediments to effective therapy include limited vector distribution on delivery, a consequence of injected virion particle trapping in the tumor extracellular matrix (ECM). To enhance virus delivery and spread, we investigated the use of the matrix metalloproteinase-9 (MMP-9) as a means to degrade collagen type IV, a major component of the ECM and basement membranes of gliomas that is absent in normal brain tissue. SK-N-AS neuroblastoma cells were transduced for constitutive, elevated expression of MMP-9, which did not enhance tumor cell migration in vitro or tumor progression in a murine xenograft brain tumor model. MMP-9 expression improved the distribution and infection of oHSV vectors in spheroid model in vitro . Furthermore, MMP9 induced a vector infection over larger areas of brain tumors in vivo . These results suggest that vector delivery and distribution in vivo can be improved by compromising the ECM, potentially enhancing oncolytic efficacy.