Systemically administered AAV9-sTRAIL combats invasive glioblastoma in a patient-derived orthotopic xenograft model

Adeno-associated virus (AAV) vectors expressing tumoricidal genes injected directly into brain tumors have shown some promise, however, invasive tumor cells are relatively unaffected. Systemic injection of AAV9 vectors provides widespread delivery to the brain and potentially the tumor/microenvironment. Here we assessed AAV9 for potential glioblastoma therapy using two different promoters driving the expression of the secreted anti-cancer agent sTRAIL as a transgene model; the ubiquitously active chicken β-actin (CBA) promoter and the neuron-specific enolase (NSE) promoter to restrict expression in brain. Intravenous injection of AAV9 vectors encoding a bioluminescent reporter showed similar distribution patterns, although the NSE promoter yielded 100-fold lower expression in the abdomen (liver), with the brain-to-liver expression ratio remaining the same. The main cell types targeted by the CBA promoter were astrocytes, neurons and endothelial cells, while expression by NSE promoter mostly occurred in neurons. Intravenous administration of either AAV9-CBA-sTRAIL or AAV9-NSE-sTRAIL vectors to mice bearing intracranial patient-derived glioblastoma xenografts led to a slower tumor growth and significantly increased survival, with the CBA promoter having higher efficacy. To our knowledge, this is the first report showing the potential of systemic injection of AAV9 vector encoding a therapeutic gene for the treatment of brain tumors. Adeno-associated virus (AAV) vectors expressing tumoricidal genes injected directly into brain tumors have shown some promise, however, invasive tumor cells are relatively unaffected. Systemic injection of AAV9 vectors provides widespread delivery to the brain and potentially the tumor/microenvironment. Here we assessed AAV9 for potential glioblastoma therapy using two different promoters driving the expression of the secreted anti-cancer agent sTRAIL as a transgene model; the ubiquitously active chicken β-actin (CBA) promoter and the neuron-specific enolase (NSE) promoter to restrict expression in brain. Intravenous injection of AAV9 vectors encoding a bioluminescent reporter showed similar distribution patterns, although the NSE promoter yielded 100-fold lower expression in the abdomen (liver), with the brain-to-liver expression ratio remaining the same. The main cell types targeted by the CBA promoter were astrocytes, neurons and endothelial cells, while expression by NSE promoter mostly occurred in neurons. Intravenous administration of either AAV9-CBA-sTRAIL or AAV9-NSE-sTRAIL vectors to mice bearing intracranial patient-derived glioblastoma xenografts led to a slower tumor growth and significantly increased survival, with the CBA promoter having higher efficacy. To our knowledge, this is the first report showing the potential of systemic injection of AAV9 vector encoding a therapeutic gene for the treatment of brain tumors. IntroductionIn recent years, adeno-associated virus (AAV) vectors have gained an increasing attention as a gene therapy vector for several diseases, some of which have made it to clinical trials.1Kotterman MA Schaffer DV Engineering adeno-associated viruses for clinical gene therapy.Nat Rev Genet. 2014; 15: 445-451Crossref PubMed Scopus (508) Google Scholar The first approved AAV-based gene therapy in the Western world is alipogene tiparvovec for the treatment of lipoprotein deficiency, which shows that this approach can be successfully and safely applied to monogenic diseases.2Salmon F Grosios K Petry H Safety profile of recombinant adeno-associated viral vectors: focus on alipogene tiparvovec (Glybera®).Expert Rev Clin Pharmacol. 2014; 7: 53-65Crossref PubMed Scopus (72) Google Scholar Additionally, AAV vectors for the treatment of more complex diseases such as heart failure have seen some success in clinical trials,3Hayward C Patel H Lyon A Gene therapy in heart failure. SERCA2a as a therapeutic target.Circ J. 2014; 78: 2577-2587Crossref PubMed Scopus (11) Google Scholar,4Zsebo K Yaroshinsky A Rudy JJ Wagner K Greenberg B Jessup M et al.Long-term effects of AAV1/SERCA2a gene transfer in patients with severe heart failure: analysis of recurrent cardiovascular events and mortality.Circ Res. 2014; 114: 101-108Crossref PubMed Scopus (235) Google Scholar and many advances are made using these vectors as cancer therapeutics.5Luo J Luo Y Sun J Zhou Y Zhang Y Yang X Adeno-associated virus-mediated cancer gene therapy: current status.Cancer Lett. 2015; 356: 347-356Abstract Full Text Full Text PDF PubMed Scopus (53) Google ScholarGlioblastoma (GBM) is the most common and highest-grade malignant primary brain tumor in adults. Despite aggressive therapies, median survival is generally just over one year following diagnosis.6Stupp R Mason WP van den Bent MJ Weller M Fisher B Taphoorn MJ European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups National Cancer Institute of Canada Clinical Trials Group et al.Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.N Engl J Med. 2005; 352: 987-996Crossref PubMed Scopus (14254) Google Scholar This underscores the need for novel treatments to be developed. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered as a potent anti-cancer agent, capable of inducing cell death in a variety of tumor cells, including GBM.7Song JH Song DK Pyrzynska B Petruk KC Van Meir EG Hao C TRAIL triggers apoptosis in human malignant glioma cells through extrinsic and intrinsic pathways.Brain Pathol. 2003; 13: 539-553Crossref PubMed Scopus (70) Google Scholar, 8Bouralexis S Findlay DM Evdokiou A Death to the bad guys: targeting cancer via Apo2L/TRAIL.Apoptosis. 2005; 10: 35-51Crossref PubMed Scopus (112) Google Scholar, 9Kuijlen JM Bremer E Mooij JJ den Dunnen WF Helfrich W Review: on TRAIL for malignant glioma therapy?.Neuropathol Appl Neurobiol. 2010; 36: 168-182Crossref PubMed Scopus (61) Google Scholar, 10Chiu TL Wang MJ Su CC The treatment of glioblastoma multiforme through activation of microglia and TRAIL induced by rAAV2-mediated IL-12 in a syngeneic rat model.J Biomed Sci. 2012; 19: 45Crossref PubMed Scopus (28) Google Scholar Direct intracranial injection of different AAV vectors into the primary tumor mass have been used for the treatment of GBM (and other brain tumors) with some success, however, due to the invasive nature of this type of cancer, tumor recurrence is typically observed showing that a vector with widespread gene delivery in the brain is required for efficient therapy.11Crommentuijn MH Maguire CA Niers JM Vandertop WP Badr CE Würdinger T et al.Intracranial AAV-sTRAIL combined with lanatoside C prolongs survival in an orthotopic xenograft mouse of invasive 10: PubMed Scopus Google Scholar, JM Wang et gene delivery by AAV vector brain and prolongs survival of by inducing cell J Sci. 2014; 15: PubMed Scopus Google Scholar, MJ K Wang E et of neurons to for treatment of Gene 2015; PubMed Scopus Google is efficient in cells in and been shown to the it an for brain and potential gene delivery to brain Y R Zhou X et of Adeno-associated viruses are in human 78: PubMed Scopus Google Scholar, K J et virus (AAV) provides gene transfer to and in the mouse and Gene 19: PubMed Scopus Google Scholar, CA MH E A et brain by Full Text Full Text PDF PubMed Scopus Google Scholar, E A AAV9 neurons and PubMed Scopus Google Scholar, S of AAV9 delivery to neurons and a of mice and 19: Full Text Full Text PDF PubMed Scopus Google Scholar, F W et of brain through systemic delivery of AAV vector expressing 2015; PubMed Scopus Google Scholar AAV9 shows the which and the potential therapeutic S of AAV9 delivery to neurons and a of mice and 19: Full Text Full Text PDF PubMed Scopus Google T A Wang et and of adeno-associated viral vectors on and vectors for B gene PubMed Scopus Google C S of AAV gene expression and in mice systemic Full Text Full Text PDF PubMed Scopus Google Scholar to restrict expression to the a brain promoter be such as the neuron-specific enolase (NSE) which is active in expression in other cell M Brain as of and PubMed Scopus Google A E T J M gene delivery to the Gene Med. PubMed Scopus Google Scholar The of the current is to systemic injection of AAV9 vector expressing a therapeutic gene TRAIL as a the of either a active promoter or neuron-specific promoter for potential therapy of tumors in the transgene expression by different promoters a similar the bioluminescent reporter the of either a active CBA promoter or neuron-specific NSE promoter and into AAV9 vector and mice were injected via the with of vector and and to the distribution of transgene delivery of vectors observed the of the the and the abdomen of mice the two showed vector yielded an of 100-fold lower in the abdomen as as the brain of mice to the that the NSE promoter be used to transgene expression and potential in the and other Despite the in transgene vectors yielded a similar expression profile in brain-to-liver expression To these mice were of either and the brain and were and for expression to of with the expression ratio by an of lower in and the brain observed with the NSE promoter to the CBA promoter with in the brain-to-liver ratio vectors promoter in AAV9 vector neurons in the brain observed expression of the vector be due to several including a lower of cells expression or To of the NSE we AAV9 vectors expressing either promoter and vectors were injected into mice a of mice were and the brain and were and for mice injected with expression of in endothelial cells, neurons and in the brain the other and as the most common cell type with expression in the brain of mice injected with were neurons these some expression observed in endothelial cells while expression with in mice mostly with and with that neurons were showed although it more widespread and in mice injected with vector to injected with vector the of cells in and the of cells showing in the of significantly more and cells in mice injected with as to cell and expression with or were injected with of or vector and and were and for the of mice injected with neurons and endothelial cells while neurons in of mice injected with vectors neurons and of in the with higher expression in the of mice injected with lower lower of cells over and the of cells and administration of vectors GBM growth in a patient-derived orthotopic xenograft mouse to the potential of AAV9 vector for systemic delivery of to brain we used the secreted of TRAIL as a transgene and it the of NSE or CBA promoter or to that sTRAIL is secreted in an active using we into an vector and cells with either vectors or as a these cells were and used to primary GBM in The on cell the other a significantly lower of cells were observed in with of GBM as to the as as in GBM with with or TRAIL in an active cells were with either or to GBM and the cell GBM cell significantly in with or to assessed systemic delivery of the brain tumor while CBA and NSE promoters to sTRAIL transgene to a promoter a similar therapeutic in of these we used an invasive patient-derived xenograft orthotopic mouse MH Maguire CA Niers JM Vandertop WP Badr CE Würdinger T et al.Intracranial AAV-sTRAIL combined with lanatoside C prolongs survival in an orthotopic xenograft mouse of invasive 10: PubMed Scopus Google H S C M et cancer of invasive glioma and treatment with virus Res. PubMed Scopus Google Scholar were injected in the with of primary GBM cells as and expressing cells mice were into treatment that a similar and and injection of of either AAV9-CBA-sTRAIL or AAV9-NSE-sTRAIL Tumor by the first the in the increased to the AAV9-NSE-sTRAIL and to the AAV9-CBA-sTRAIL treatment and mice in the tumor which were due to showed that tumors in the AAV9-NSE-sTRAIL and AAV9-CBA-sTRAIL to with the showing more were in the AAV9-NSE-sTRAIL and AAV9-CBA-sTRAIL delivery of invasive GBM tumor growth in the brain. were injected with patient-derived GBM expressing mice were into which were injected with of either AAV9-NSE-sTRAIL or used to tumor the of the A of a mouse is shown different survival for the different treatment and of brain A of a mouse is shown analysis showed that an analysis showed that the survival of mice significantly that of mice with AAV9-NSE-sTRAIL and with AAV9-CBA-sTRAIL This shows that sTRAIL treatment using AAV9 vectors either promoter a therapeutic a for survival in mice with AAV9-CBA-sTRAIL as to the two the that showed a tumor in mice with and that these mice survival for the while mice with AAV9-NSE-sTRAIL or AAV9-CBA-sTRAIL a median survival of and a of mice with AAV9-CBA-sTRAIL to the of the This a for survival in mice with the vector using the CBA promoter over the NSE To our knowledge, this is the first report showing systemic injection of an AAV vector to tumors in the we analysis using and for cell on of mice as TRAIL and AAV9 is to cells in the we on to this therapy analysis in the different tumors were the injection in the of mice the tumor cells were on of mice in the AAV9-NSE-sTRAIL or AAV9-CBA-sTRAIL and observed tumor in brain cells of AAV as a gene therapy delivery vector in MA Schaffer DV Engineering adeno-associated viruses for clinical gene therapy.Nat Rev Genet. 2014; 15: 445-451Crossref PubMed Scopus (508) Google Scholar The of AAV9 to the administration this for gene therapy of the the CA MH E A et brain by Full Text Full Text PDF PubMed Scopus Google S of AAV9 delivery to neurons and a of mice and 19: Full Text Full Text PDF PubMed Scopus Google Scholar GBM is an aggressive of primary brain cancer that is to The of death on the of GBM cells a potential the and to the are a using recombinant TRAIL for therapy in the H E and of necrosis factor-related apoptosis-inducing ligand in human PubMed Scopus Google H S van et of a apoptosis-inducing and a TRAIL for clinical J Pharmacol. 2012; PubMed Scopus Google Scholar AAV vectors encoding TRAIL have been for the treatment of many of cancer, although most or M Y H S Y et of TRAIL expression combined with on and cell PubMed Scopus Google Scholar, A T et expression of TRAIL in human cancer to tumor PubMed Scopus Google Scholar, J Y MH F et of TRAIL apoptosis in human and growth of tumor xenografts in Res. 2005; PubMed Scopus Google Scholar systemic Y H Zhang J S Y TRAIL gene expression by promoter human growth in Sci. PubMed Scopus Google H Y S R adeno-associated gene therapy human growth in 2005; PubMed Scopus Google Scholar of the systemic delivery is due to and brain distribution of many AAV vectors and TRAIL MH Maguire CA Niers JM Vandertop WP Badr CE Würdinger T et al.Intracranial AAV-sTRAIL combined with lanatoside C prolongs survival in an orthotopic xenograft mouse of invasive 10: PubMed Scopus Google C S of AAV gene expression and in mice systemic Full Text Full Text PDF PubMed Scopus Google H E and of necrosis factor-related apoptosis-inducing ligand in human PubMed Scopus Google Scholar Here we used AAV9 vectors for delivery of sTRAIL a transgene to the primary tumor mass and tumor cells in the brain. effects are to tumor J R and a death for PubMed Scopus Google Scholar, K R R J et for the ligand PubMed Scopus Google Scholar, A M et of apoptosis by a of and PubMed Scopus Google Scholar of TRAIL or other transgene expression in the C S of AAV gene expression and in mice systemic Full Text Full Text PDF PubMed Scopus Google E et of vector on T and B cell in gene Gene 13: PubMed Scopus Google Scholar a to M K et induced in human by tumor necrosis factor-related apoptosis-inducing Med. 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This is due to the that in AAV9 E A AAV9 neurons and PubMed Scopus Google Scholar expression to mostly neurons in the we the transgene expression in the brain. we observed that while the CBA promoter to expression in most cell types in the most and endothelial cells, the NSE promoter to a more expression in neurons with expression in endothelial cells and expression in the the NSE promoter be on a the CBA in with other J and in the combined targeting and transgene Full Text Full Text PDF PubMed Scopus Google R M A et of expression with adeno-associated virus gene PubMed Scopus Google Scholar the we be to expression of transgene in the brain and lower expression in the by into the of the transgene as H C Su et injection as as and Gene therapy in Full Text Full Text PDF PubMed Scopus Google have shown that capable of primary GBM tumor mass in a mouse however, vector injection to invasive cells, which to the of and a tumor in the mouse brain to tumor MH Maguire CA Niers JM Vandertop WP Badr CE Würdinger T et al.Intracranial AAV-sTRAIL combined with lanatoside C prolongs survival in an orthotopic xenograft mouse of invasive 10: PubMed Scopus Google Scholar to intracranial a administration of a therapeutic vector with widespread be it the primary tumor mass as as tumor cells in the brain. a injection of either AAV9-CBA-sTRAIL or AAV9-NSE-sTRAIL vectors to a significantly slower tumor growth and in survival as to mice with a in slower tumor growth and in survival of mice with AAV9-CBA-sTRAIL as to AAV9-NSE-sTRAIL were showing the of neuron-specific promoter with lower in aggressive GBM To our knowledge, this is the first report showing that systemic injection of an AAV vector tumors in the brain using a promoter with lower of the brain is a in GBM this therapy the of GBM cells to other of the the primary tumor and mice Additionally, to therapy is a for the treatment of A and TRAIL in glioblastoma multiforme 2005; PubMed Scopus Google Scholar, C F A Van Meir EG et and of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in human malignant glioma Res. Google Scholar, of a TRAIL by a for PubMed Scopus (28) Google Scholar a relatively of A higher of or of combined with CE T J Niers JM M A et C glioblastoma cells to tumor necrosis factor-related apoptosis-inducing ligand and an cell death 13: PubMed Scopus Google Scholar, malignant human glioma cells to by of the Cancer 10: PubMed Scopus Google Scholar, J S and a for of Rev Full Text Full Text PDF PubMed Scopus Google Scholar, M JJ death expression by in human with tumor necrosis factor-related apoptosis-inducing ligand in and in Res. Google Scholar a for the invasive growth of GBM and intrinsic or TRAIL TRAIL to have the as of in as observed in the promoter be for TRAIL expression in such as the in transgene expression of TRAIL be a due to AAV or the E et of vector on T and B cell in gene Gene 13: PubMed Scopus Google B M JJ et of in by and by the Med. PubMed Scopus Google Scholar in patients with X MJ M F M et of tumor necrosis factor-related apoptosis-inducing ligand in human PubMed Scopus Google AAV9 encoding a therapeutic is a approach to GBM using higher vector different transgene expression combined with to a more survival and vector by CA et growth of brain tumors by a of Full Text Full Text PDF PubMed Scopus Google Scholar and CA H et of adeno-associated virus for glioma cell 2010; PubMed Scopus Google Scholar with and with The vector been X Y of human by systemic administration of a recombinant gene encoding the Full Text Full Text PDF PubMed Scopus Google CA MH Niers JM M J et for in of Full Text Full Text PDF PubMed Scopus Google Scholar this sTRAIL by using the following and sTRAIL with and were into a and viral vector cells, for AAV were in with of complex glioblastoma H S C M et cancer of invasive glioma and treatment with virus Res. PubMed Scopus Google Scholar were as in with with recombinant growth growth and cells were vectors were as M Adeno-associated virus vectors with are more efficient or for widespread gene delivery to the mouse PubMed Scopus Google Scholar of cells using used with transgene and for in or for in the cells were by and AAV using in of of sTRAIL cells were in a The cells were with or have shown that the NSE promoter is active in CA et growth of brain tumors by a of Full Text Full Text PDF PubMed Scopus Google Scholar The cell cells were in of a cells and to the cells for in of cell and in active cells using the as of using a and were used to in the and cell in treatment of the as a with the and were approved by the on Research and to and mice of were and mouse in a the in a with and with were injected with a of of either or or of or or of AAV9-CBA-sTRAIL or AAV9-NSE-sTRAIL GBM mice were with a of and in were in a and injected with cells using a to a with a the following in the of vectors or tumor expression in mice using a with an were with in and the injection of using the the and of mice were for The used to a of the abdomen or the of mice and to of vector mice were and by injection with an of and in and brain were on and of in a Fisher by a and of and using the for The the to the for The to to in to in to be in the of the the of to a The to of to and the a of and for were of the for and injection of or mice were and with for to the by for to The brain and mouse were for in and to in for for were in using a and in a the brain or were in two or to a on and on The were using in and with in for in in and for in for in with in were using a and applied and were with a the were a with an for using the type on The of cells for cell type and over the in analysis using A considered To promoter or a analysis of used by a to two were using an analysis a analysis of by a using and to or IntroductionIn recent years, adeno-associated virus (AAV) vectors have gained an increasing attention as a gene therapy vector for several diseases, some of which have made it to clinical trials.1Kotterman MA Schaffer DV Engineering adeno-associated viruses for clinical gene therapy.Nat Rev Genet. 2014; 15: 445-451Crossref PubMed Scopus (508) Google Scholar The first approved AAV-based gene therapy in the Western world is alipogene tiparvovec for the treatment of lipoprotein deficiency, which shows that this approach can be successfully and safely applied to monogenic diseases.2Salmon F Grosios K Petry H Safety profile of recombinant adeno-associated viral vectors: focus on alipogene tiparvovec (Glybera®).Expert Rev Clin Pharmacol. 2014; 7: 53-65Crossref PubMed Scopus (72) Google Scholar Additionally, AAV vectors for the treatment of more complex diseases such as heart failure have seen some success in clinical trials,3Hayward C Patel H Lyon A Gene therapy in heart failure. SERCA2a as a therapeutic target.Circ J. 2014; 78: 2577-2587Crossref PubMed Scopus (11) Google Scholar,4Zsebo K Yaroshinsky A Rudy JJ Wagner K Greenberg B Jessup M et al.Long-term effects of AAV1/SERCA2a gene transfer in patients with severe heart failure: analysis of recurrent cardiovascular events and mortality.Circ Res. 2014; 114: 101-108Crossref PubMed Scopus (235) Google Scholar and many advances are made using these vectors as cancer therapeutics.5Luo J Luo Y Sun J Zhou Y Zhang Y Yang X Adeno-associated virus-mediated cancer gene therapy: current status.Cancer Lett. 2015; 356: 347-356Abstract Full Text Full Text PDF PubMed Scopus (53) Google ScholarGlioblastoma (GBM) is the most common and highest-grade malignant primary brain tumor in adults. Despite aggressive therapies, median survival is generally just over one year following diagnosis.6Stupp R Mason WP van den Bent MJ Weller M Fisher B Taphoorn MJ European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups National Cancer Institute of Canada Clinical Trials Group et al.Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.N Engl J Med. 2005; 352: 987-996Crossref PubMed Scopus (14254) Google Scholar This underscores the need for novel treatments to be developed. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered as a potent anti-cancer agent, capable of inducing cell death in a variety of tumor cells, including GBM.7Song JH Song DK Pyrzynska B Petruk KC Van Meir EG Hao C TRAIL triggers apoptosis in human malignant glioma cells through extrinsic and intrinsic pathways.Brain Pathol. 2003; 13: 539-553Crossref PubMed Scopus (70) Google Scholar, 8Bouralexis S Findlay DM Evdokiou A Death to the bad guys: targeting cancer via Apo2L/TRAIL.Apoptosis. 2005; 10: 35-51Crossref PubMed Scopus (112) Google Scholar, 9Kuijlen JM Bremer E Mooij JJ den Dunnen WF Helfrich W Review: on TRAIL for malignant glioma therapy?.Neuropathol Appl Neurobiol. 2010; 36: 168-182Crossref PubMed Scopus (61) Google Scholar, 10Chiu TL Wang MJ Su CC The treatment of glioblastoma multiforme through activation of microglia and TRAIL induced by rAAV2-mediated IL-12 in a syngeneic rat model.J Biomed Sci. 2012; 19: 45Crossref PubMed Scopus (28) Google Scholar Direct intracranial injection of different AAV vectors into the primary tumor mass have been used for the treatment of GBM (and other brain tumors) with some success, however, due to the invasive nature of this type of cancer, tumor recurrence is typically observed showing that a vector with widespread gene delivery in the brain is required for efficient therapy.11Crommentuijn MH Maguire CA Niers JM Vandertop WP Badr CE Würdinger T et al.Intracranial AAV-sTRAIL combined with lanatoside C prolongs survival in an orthotopic xenograft mouse of invasive 10: PubMed Scopus Google Scholar, JM Wang et gene delivery by AAV vector brain and prolongs survival of by inducing cell J Sci. 2014; 15: PubMed Scopus Google Scholar, MJ K Wang E et of neurons to for treatment of Gene 2015; PubMed Scopus Google is efficient in cells in and been shown to the it an for brain and potential gene delivery to brain Y R Zhou X et of Adeno-associated viruses are in human 78: PubMed Scopus Google Scholar, K J et virus (AAV) provides gene transfer to and in the mouse and Gene 19: PubMed Scopus Google Scholar, CA MH E A et brain by Full Text Full Text PDF PubMed Scopus Google Scholar, E A AAV9 neurons and PubMed Scopus Google Scholar, S of AAV9 delivery to neurons and a of mice and 19: Full Text Full Text PDF PubMed Scopus Google Scholar, F W et of brain through systemic delivery of AAV vector expressing 2015; PubMed Scopus Google Scholar AAV9 shows the which and the potential therapeutic S of AAV9 delivery to neurons and a of mice and 19: Full Text Full Text PDF PubMed Scopus Google T A Wang et and of adeno-associated viral vectors on and vectors for B gene PubMed Scopus Google C S of AAV gene expression and in mice systemic Full Text Full Text PDF PubMed Scopus Google Scholar to restrict expression to the a brain promoter be such as the neuron-specific enolase (NSE) which is active in expression in other cell M Brain as of and PubMed Scopus Google A E T J M gene delivery to the Gene Med. PubMed Scopus Google Scholar The of the current is to systemic injection of AAV9 vector expressing a therapeutic gene TRAIL as a the of either a active promoter or neuron-specific promoter for potential therapy of tumors in the brain.

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