{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T12:24:16Z","timestamp":1769603056169,"version":"3.49.0"},"reference-count":45,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T00:00:00Z","timestamp":1642032000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["NS081146"],"award-info":[{"award-number":["NS081146"]}]},{"name":"National Institute of Health","award":["NS088013"],"award-info":[{"award-number":["NS088013"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Schwannomas are tumors derived from Schwann-lineage cells, cells that protect and support myelinated nerves in the peripheral nervous system. They are typically slow-growing, encapsulated and benign. These tumors develop along peripheral, spinal and cranial nerves causing pain, sensory-motor dysfunction and death. Primary treatment for schwannoma is operative resection which can be associated with significant morbidity. Pharmacotherapy is largely restricted to bevacizumab, which has minimal or no efficacy for many patients and can be associated with treatment-limiting adverse effects. Given the suffering and morbidity associated with schwannoma and the paucity of therapeutic options, there is an urgent need for safe and effective therapies for schwannomas. We previously demonstrated that adeno-associated virus serotype 1 (AAV1) vector mediated delivery of the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) under the control of the P0 promoter, produced a prolonged reduction in tumor volume and tumor-associated pain in human xenograft and mouse syngeneic schwannoma models. Here, we present data essential for the translation of our AAV1-P0-ASC schwannoma gene therapy to clinical trials. We determine the minimum effective dose of AAV1-P0-hASC required to induce an anti-tumor effect in the xenograft human-schwannoma model. We also show that the presence of preexisting AAV1 immunity does not alter the antitumor efficacy of AAV-P0-mASC in a syngeneic mouse schwannoma model. Furthermore, the maximum deliverable intratumoral dose of AAV1-P0-ASC was not associated with neuronal toxicity in immunocompetent mice. Taken together, these safety and efficacy data support the translation of the AAV1-P0-ASC schwannoma gene therapy strategy to clinical trials.<\/jats:p>","DOI":"10.3390\/ijms23020819","type":"journal-article","created":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T10:57:37Z","timestamp":1642071457000},"page":"819","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Schwannoma Gene Therapy via Adeno-Associated Viral Vector Delivery of Apoptosis-Associated Speck-like Protein Containing CARD (ASC): Preclinical Efficacy and Safety"],"prefix":"10.3390","volume":"23","author":[{"given":"Sherif G.","family":"Ahmed","sequence":"first","affiliation":[{"name":"Department of Anesthesiology, Critical Care, Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Casey A.","family":"Maguire","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shiliang Alice","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Critical Care, Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4586-1723","authenticated-orcid":false,"given":"Gary J.","family":"Brenner","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Critical Care, Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,13]]},"reference":[{"key":"ref_1","first-page":"E81","article-title":"The neurofibromatoses. Part 2: NF2 and schwannomatosis","volume":"6","author":"Plotkin","year":"2009","journal-title":"Rev. Neurol. Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1212\/WNL.54.1.71","article-title":"Population-based analysis of sporadic and type 2 neurofibromatosis-associated meningiomas and schwannomas","volume":"54","author":"Antinheimo","year":"2000","journal-title":"Neurology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/1750-1172-4-16","article-title":"Neurofibromatosis type 2 (NF2): A clinical and Molecular review","volume":"4","author":"Evans","year":"2009","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.3171\/2015.7.JNS151056","article-title":"Malignant peripheral nerve sheath tumors of the eighth cranial nerve arising without prior irradiation","volume":"125","author":"Carlson","year":"2016","journal-title":"J. Neurosurg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1055\/s-0036-1579766","article-title":"Neurofibromatosis: A Review of NF1, NF2, and Schwannomatosis","volume":"5","author":"Kresak","year":"2016","journal-title":"J. Pediatr. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1016\/j.otc.2021.05.004","article-title":"Biological Treatments of Neurofibromatosis Type 2 and Other Skull Base Disorders","volume":"54","author":"Raskin","year":"2021","journal-title":"Otolaryngol. Clin. N. Am."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3483","DOI":"10.1158\/0008-5472.CAN-09-3107","article-title":"Anti-vascular endothelial growth factor therapies as a novel therapeutic approach to treating neurofibromatosis-related tumors","volume":"70","author":"Wong","year":"2010","journal-title":"Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Chang, L.S., Oblinger, J.L., Smith, A.E., Ferrer, M., Angus, S.P., Hawley, E., Petrilli, A.M., Beauchamp, R.L., Riecken, L.B., and Erdin, S. (2021). Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0252048"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1159\/000365156","article-title":"Incidence and relevance of proteinuria in bevacizumab-treated patients: Pooled analysis from randomized controlled trials","volume":"40","author":"Lafayette","year":"2014","journal-title":"Am. J. Nephrol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/s11060-019-03234-8","article-title":"Efficacy and safety of bevacizumab for vestibular schwannoma in neurofibromatosis type 2: A systematic review and meta-analysis of treatment outcomes","volume":"144","author":"Lu","year":"2019","journal-title":"J. Neurooncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"103148","DOI":"10.1016\/j.amjoto.2021.103148","article-title":"Reliability and toxicity of bevacizumab for neurofibromatosis type 2-related vestibular schwannomas: A systematic review and meta-analysis","volume":"42","author":"Shi","year":"2021","journal-title":"Am. J. Otolaryngol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1089\/hum.2012.094","article-title":"Regression of schwannomas induced by adeno-associated virus-mediated delivery of caspase-1","volume":"24","author":"Prabhakar","year":"2013","journal-title":"Hum. Gene Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1038\/s41417-018-0077-3","article-title":"Schwannoma gene therapy by adeno-associated virus delivery of the pore-forming protein Gasdermin-D","volume":"26","author":"Ahmed","year":"2019","journal-title":"Cancer Gene Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1093\/neuonc\/noz065","article-title":"Gene therapy with apoptosis-associated speck-like protein (ASC), a newly described schwannoma tumor suppressor, inhibits schwannoma growth in vivo","volume":"21","author":"Ahmed","year":"2019","journal-title":"Neuro Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.jneumeth.2019.05.007","article-title":"Developing myelin specific promoters for schwannoma gene therapy","volume":"323","author":"Ahmed","year":"2019","journal-title":"J. Neurosci. Methods"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/cgt.2009.71","article-title":"Imaging and therapy of experimental schwannomas using HSV amplicon vector-encoding apoptotic protein under Schwann cell promoter","volume":"17","author":"Prabhakar","year":"2010","journal-title":"Cancer Gene Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.cell.2010.01.040","article-title":"The inflammasomes","volume":"140","author":"Schroder","year":"2010","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1023\/B:APPT.0000012117.32430.0c","article-title":"TMS1\/ASC: The cancer connection","volume":"9","author":"McConnell","year":"2004","journal-title":"Apoptosis Int. J. Program. Cell Death"},{"key":"ref_19","first-page":"6243","article-title":"Activation of a caspase-9-mediated apoptotic pathway by subcellular redistribution of the novel caspase recruitment domain protein TMS1","volume":"60","author":"McConnell","year":"2000","journal-title":"Cancer Res."},{"key":"ref_20","first-page":"3919","article-title":"Methylation-mediated silencing of TMS1 in pancreatic cancer and its potential contribution to chemosensitivity","volume":"30","author":"Ramachandran","year":"2010","journal-title":"Anticancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"22706","DOI":"10.18632\/oncotarget.4256","article-title":"Epigenetic inactivation of the candidate tumor suppressor gene ASC\/TMS1 in human renal cell carcinoma and its role as a potential therapeutic target","volume":"6","author":"Liu","year":"2015","journal-title":"Oncotarget"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1089\/hum.2009.182","article-title":"Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: Implications for gene therapy using AAV vectors","volume":"21","author":"Boutin","year":"2010","journal-title":"Hum. Gene Ther."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1089\/hgtb.2012.243","article-title":"Pre-existing anti-adeno-associated virus antibodies as a challenge in AAV gene therapy","volume":"24","author":"Joergensen","year":"2013","journal-title":"Hum. Gene Ther. Methods"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1086\/595830","article-title":"Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses","volume":"199","author":"Calcedo","year":"2009","journal-title":"J. Infect. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"658399","DOI":"10.3389\/fimmu.2021.658399","article-title":"Anti-AAV Antibodies in AAV Gene Therapy: Current Challenges and Possible Solutions","volume":"12","author":"Weber","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.jneumeth.2010.10.021","article-title":"A novel imaging-compatible sciatic nerve schwannoma model","volume":"195","author":"Saydam","year":"2011","journal-title":"J. Neurosci. Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/0304-3959(88)90026-7","article-title":"A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia","volume":"32","author":"Hargreaves","year":"1988","journal-title":"Pain"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1038\/nn1916","article-title":"Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors","volume":"10","author":"Agarwal","year":"2007","journal-title":"Nat. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.1080\/00207450902984002","article-title":"Rotarod impairment: Catalepsy-like screening test for antipsychotic side effects","volume":"119","author":"Kirschbaum","year":"2009","journal-title":"Int. J. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7598","DOI":"10.1016\/j.biomaterials.2014.05.032","article-title":"Naturally enveloped AAV vectors for shielding neutralizing antibodies and robust gene delivery in vivo","volume":"35","author":"Gyorgy","year":"2014","journal-title":"Biomaterials"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/978-1-61779-370-7_11","article-title":"Measuring immune responses to recombinant AAV gene transfer","volume":"807","author":"Martino","year":"2011","journal-title":"Methods Mol. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1097\/BRS.0000000000001232","article-title":"Risk Factors for Recurrence of Surgically Treated Conventional Spinal Schwannomas: Analysis of 169 Patients From a Multicenter International Database","volume":"41","author":"Fehlings","year":"2016","journal-title":"Spine"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1590","DOI":"10.1038\/sj.cdd.4402194","article-title":"The pyroptosome: A supramolecular assembly of ASC dimers mediating inflammatory cell death via caspase-1 activation","volume":"14","author":"Wu","year":"2007","journal-title":"Cell Death Differ."},{"key":"ref_34","first-page":"2095","article-title":"Down-regulation of bcl-2 by p53 in breast cancer cells","volume":"54","author":"Haldar","year":"1994","journal-title":"Cancer Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1038\/sj.leu.2402090","article-title":"Phosphorylation of Bcl2 and regulation of apoptosis","volume":"15","author":"Ruvolo","year":"2001","journal-title":"Leukemia"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1038\/sj.cgt.7701037","article-title":"Treatment of implantable NF2 schwannoma tumor models with oncolytic herpes simplex virus G47Delta","volume":"14","author":"Prabhakar","year":"2007","journal-title":"Cancer Gene Ther."},{"key":"ref_37","first-page":"475","article-title":"Establishment and characterization of a schwannoma cell line from a patient with neurofibromatosis 2","volume":"20","author":"Hung","year":"2002","journal-title":"Int. J. Oncol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3856","DOI":"10.1158\/1078-0432.CCR-12-3167","article-title":"Therapeutic potential of HSP90 inhibition for neurofibromatosis type 2","volume":"19","author":"Tanaka","year":"2013","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1038\/sj.gt.3302134","article-title":"Adeno-associated virus terminal repeat (TR) mutant generates self-complementary vectors to overcome the rate-limiting step to transduction in vivo","volume":"10","author":"McCarty","year":"2003","journal-title":"Gene Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1016\/j.neuroscience.2005.11.057","article-title":"Adeno-associated virus vectors serotyped with AAV8 capsid are more efficient than AAV-1 or -2 serotypes for widespread gene delivery to the neonatal mouse brain","volume":"138","author":"Broekman","year":"2006","journal-title":"Neuroscience"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1523\/JNEUROSCI.3985-08.2009","article-title":"Loss of modifier of cell adhesion reveals a pathway leading to axonal degeneration","volume":"29","author":"Chen","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1038\/sj.neo.7900265","article-title":"Detection of spontaneous schwannomas by MRI in a transgenic murine model of neurofibromatosis type 2","volume":"4","author":"Messerli","year":"2002","journal-title":"Neoplasia"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"14646","DOI":"10.1523\/JNEUROSCI.2536-09.2009","article-title":"Overexpression of the wild-type SPT1 subunit lowers desoxysphingolipid levels and rescues the phenotype of HSAN1","volume":"29","author":"Eichler","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"87","DOI":"10.4103\/0976-500X.72350","article-title":"Blood sample collection in small laboratory animals","volume":"1","author":"Parasuraman","year":"2010","journal-title":"J. Pharmacol. Pharmacother."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.jada.2011.09.037","article-title":"Publishing nutrition research: A review of multivariate techniques\u2014Part 2: Analysis of variance","volume":"112","author":"Harris","year":"2012","journal-title":"J. Acad. Nutr. Diet."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/2\/819\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:28:53Z","timestamp":1760365733000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/2\/819"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,13]]},"references-count":45,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["ijms23020819"],"URL":"https:\/\/doi.org\/10.3390\/ijms23020819","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,13]]}}}