title: Late responses to adenoviral-mediated transfer of the aquaporin-1 gene for radiation-induced salivary hypofunction.
abstract: We evaluated late effects of AdhAQP1 administration in five subjects in a clinical trial for radiation-induced salivary hypofunction (http://www.clinicaltrials.gov/ct/show/NCT00372320?order=). All were identified as initially responding to human aquaporin-1 (hAQP1) gene transfer. They were followed for 3-4 years after AdhAQP1 delivery to one parotid gland. At intervals we examined salivary flow, xerostomic symptoms, saliva composition, vector presence and efficacy in the targeted gland, clinical laboratory data and adverse events. All displayed marked increases (71-500% above baseline) in parotid flow 3-4.7 years after treatment, with improved symptoms for ~2-3 years. There were some changes in [Na+] and [Cl-] consistent with elevated salivary flow, but no uniform changes in secretion of key parotid proteins. There were no clinically significant adverse events, nor consistent negative changes in laboratory parameters. One subject underwent a core needle biopsy of the targeted parotid gland 3.1 years post treatment and displayed evidence of hAQP1 protein in acinar, but not duct, cell membranes. All subjects responding to hAQP1 gene transfer initially had benefits for much longer times. First-generation adenoviral vectors typically yield transit effects, but these data show beneficial effects can continue years after parotid gland delivery.
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
authors.forename: I
authors.initials: I
authors.lastname: Alevizos
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Zheng
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
authors.forename: A P
authors.initials: AP
authors.lastname: Cotrim
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
authors.forename: L
authors.initials: L
authors.lastname: McCullagh
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Billings
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Goldsmith
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Tandon
authors.affiliation: Department of Molecular and Cell Biology, Boston University, Boston, MA, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Helmerhorst
authors.affiliation: Secretory Mechanisms and Dysfunction Section, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Catalán
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.|Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Danielides
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
authors.forename: P
authors.initials: P
authors.lastname: Perez
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
authors.forename: N P
authors.initials: NP
authors.lastname: Nikolov
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Chiorini
authors.affiliation: Secretory Mechanisms and Dysfunction Section, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Melvin
authors.affiliation: Department of Molecular and Cell Biology, Boston University, Boston, MA, USA.
authors.forename: F G
authors.initials: FG
authors.lastname: Oppenheim
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.|Clinical Development, MedImmune, Gaithersburg, MD, USA.
authors.forename: G G
authors.initials: GG
authors.lastname: Illei
authors.affiliation: Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Baum
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D051398:Aquaporin 1 / Q000235:genetics* / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D015316:Genetic Therapy / Q000009:adverse effects*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D011878:Radiotherapy / Q000009:adverse effects; D012469:Salivary Glands / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D014987:Xerostomia / Q000209:etiology / Q000628:therapy*
chemical_list: D002712:Chlorides; D051398:Aquaporin 1; D012964:Sodium