CERE-120 Prevents Irradiation-Induced Hypofunction and Restores Immune Homeostasis in Porcine Salivary Glands

Isabelle M A Lombaert; Vaishali N Patel; Christina E Jones; Derrick C Villier; Ashley E Canada; Matthew R Moore; Elsa Berenstein; Changyu Zheng; Corinne M Goldsmith; John A Chorini; Daniel Martin; Lee Zourelias; Mark G Trombetta; Paul C Edwards; Kathleen Meyer; Dale Ando; Michael J Passineau; Matthew P Hoffman

doi:10.1016/j.omtm.2020.07.016

CERE-120 Prevents Irradiation-Induced Hypofunction and Restores Immune Homeostasis in Porcine Salivary Glands

Mol Ther Methods Clin Dev. 2020 Jul 31:18:839-855. doi: 10.1016/j.omtm.2020.07.016. eCollection 2020 Sep 11.

Authors

Isabelle M A Lombaert^{1

2

3}, Vaishali N Patel¹, Christina E Jones¹, Derrick C Villier¹, Ashley E Canada¹, Matthew R Moore¹, Elsa Berenstein¹, Changyu Zheng⁴, Corinne M Goldsmith⁴, John A Chorini⁵, Daniel Martin⁶, Lee Zourelias⁷, Mark G Trombetta⁸, Paul C Edwards⁹, Kathleen Meyer¹⁰, Dale Ando¹⁰, Michael J Passineau⁷, Matthew P Hoffman¹

Affiliations

¹ Matrix and Morphogenesis Section, National Institute of Dental and Craniofacial Research, NIH, DHHS, Bethesda, MD 20892, USA.
² Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA.
³ Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109, USA.
⁴ Translational Research Core, NIDCR, NIH, DHHS, Bethesda, MD 20892, USA.
⁵ Adeno-Associated Virus Section, NIDCR, NIH, DHHS, Bethesda, MD 20892, USA.
⁶ Genomics and Computational Biology Core, NIDCR, NIH, DHHS, Bethesda, MD 20892, USA.
⁷ Gene Therapy Program, Department of Medicine, Division of Cardiovascular Medicine, Allegheny Health Network, Pittsburg, PA 15212, USA.
⁸ Department of Oncology, Division of Radiation Oncology, Allegheny Health Network, Pittsburg, PA 15212, USA.
⁹ Department of Oral Pathology, Medicine, and Radiology, Indiana University School of Dentistry, Indianapolis, IN 46202, USA.
¹⁰ Sangamo BioSciences, Inc., 501 Canal Blvd., Richmond, CA 94804.

Abstract

Salivary gland hypofunction causes significant morbidity and loss of quality of life for head and neck cancer patients treated with radiotherapy. Preventing hypofunction is an unmet therapeutic need. We used an adeno-associated virus serotype 2 (AAV2) vector expressing the human neurotrophic factor neurturin (CERE-120) to treat murine submandibular glands either pre- or post-irradiation (IR). Treatment with CERE-120 pre-IR, not post-IR, prevented hypofunction. RNA sequencing (RNA-seq) analysis showed reduced gene expression associated with fibrosis and the innate and humoral immune responses. We then used a minipig model with CERE-120 treatment pre-IR and also compared outcomes of the contralateral non-IR gland. Analysis of gene expression, morphology, and immunostaining showed reduced IR-related immune responses and improved secretory mechanisms. CERE-120 prevented IR-induced hypofunction and restored immune homeostasis, and there was a coordinated contralateral gland response to either damage or treatment. CERE-120 gene therapy is a potential treatment for head and neck cancer patients to influence communication among neuronal, immune, and epithelial cells to prevent IR-induced salivary hypofunction and restore immune homeostasis.

Keywords: AAV-neurturin; CERE-120; fibrosis; gene therapy; head and neck cancer; humoral immunity; innate immunity; irradiation damage; salivary gland; salivary hypofunction.

Abstract

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