Early responses to adenoviral-mediated transfer of the aquaporin-1 cDNA for radiation-induced salivary hypofunction

Early responses to adenoviral-mediated transfer of the aquaporin-1 cDNA for radiation-induced salivary hypofunction

1. Bruce J. Baum^a,¹,
2. Ilias Alevizos^a,
3. Changyu Zheng^a,
4. Ana P. Cotrim^a,
5. Shuying Liu^a,
6. Linda McCullagh^a,
7. Corinne M. Goldsmith^a,
8. Peter D. Burbelo^b,
9. Deborah E. Citrin^c,
10. James B. Mitchell^d,
11. Liesl K. Nottingham^e,
12. Susan F. Rudy^e,
13. Carter Van Waes^e,
14. Millie A. Whatley^f,
15. Jaime S. Brahim^g,
16. John A. Chiorini^a,
17. Stamatina Danielides^a,
18. R. James Turner^a,
19. Nicholas J. Patronas^h,
20. Clara C. Chen^f,
21. Nikolay P. Nikolov^a, and
22. Gabor G. Illei^a

+ Author Affiliations

1. ^aMolecular Physiology and Therapeutics Branch, and
2. ^bNeurobiology and Pain Therapeutics Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892;
3. ^cRadiation Oncology Branch and
4. ^dRadiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892;
5. ^eHead and Neck Surgery Branch, National Institute of Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892;
6. ^fNuclear Medicine Section and
7. ^hSection on Neuroradiology, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, Bethesda, MD 20892; and
8. ^gDepartment of Oral-Maxillofacial Surgery, University of Maryland, Baltimore, MD 21201

1. Edited by C. Thomas Caskey, Baylor College of Medicine, Houston, TX, and approved September 27, 2012 (received for review June 21, 2012)

Abstract

No conventional therapy exists for salivary hypofunction in surviving head and neck cancer patients with Radiation Therapy Oncology Group late grade 2–3 toxicity. We conducted a phase I clinical trial to test the safety and biologic efficacy of serotype 5, adenoviral-mediated aquaporin-1 cDNA transfer to a single previously irradiated parotid gland in 11 subjects using an open label, single-dose, dose-escalation design (AdhAQP1 vector; four dose tiers from 4.8 × 10⁷ to 5.8 × 10⁹ vector particles per gland). Treated subjects were followed at scheduled intervals. Multiple safety parameters were measured and biologic efficacy was evaluated with measurements of parotid salivary flow rate. Symptoms were assessed with a visual analog scale. All subjects tolerated vector delivery and study procedures well over the 42-d study period reported. No deaths, serious adverse events, or dose-limiting toxicities occurred. Generally, few adverse events occurred, and all were considered mild or moderate. No consistent changes were found in any clinical chemistry and hematology parameters measured. Objective responses were seen in six subjects, all at doses <5 .8=".8" 10="10" sup="sup">9

vector particles per gland. Five of these six subjects also experienced subjective improvement in xerostomia. AdhAQP1 vector delivery to a single parotid gland was safe and transfer of the hAQP1 cDNA increased parotid flow and relieved symptoms in a subset of subjects.

• gene therapy
• radiation damage
• salivary glands
• dry mouth
• water channel

Footnotes

• ↵¹To whom correspondence should be addressed. E-mail: bbaum@mail.nih.gov.

• Author contributions: B.J.B., I.A., C.Z., D.E.C., J.B.M., J.S.B., J.A.C., R.J.T., C.C.C., and G.G.I. designed research; B.J.B., I.A., C.Z., A.P.C., S.L., L.M., C.M.G., P.D.B., L.K.N., S.F.R., C.V.W., M.A.W., J.S.B., S.D., N.J.P., C.C.C., N.P.N., and G.G.I. performed research; B.J.B., I.A., C.Z., A.P.C., S.L., L.M., P.D.B., D.E.C., J.B.M., C.V.W., J.A.C., S.D., R.J.T., N.J.P., C.C.C., N.P.N., and G.G.I. analyzed data; and B.J.B., I.A., C.Z., A.P.C., S.L., L.M., C.M.G., P.D.B., D.E.C., J.B.M., L.K.N., S.F.R., C.V.W., M.A.W., J.S.B., J.A.C., S.D., R.J.T., N.J.P., C.C.C., N.P.N., and G.G.I. wrote the paper.
• The authors declare no conflict of interest.
• This article is a PNAS Direct Submission.
• This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1210662109/-/DCSupplemental.