Last updated on March 2019

Safety of a Single Administration of AAV2hAQP1 an Adeno-Associated Viral Vector Encoding Human Aquaporin-1 to One Parotid Salivary Gland in People With Irradiation-Induced Parotid Salivary Hypofunction


Brief description of study

Background
  • Radiation can cause the parotid salivary glands to make less saliva (dry mouth). This can cause problems like infections and tooth decay. Researchers hope a new drug can help people with dry mouth caused by radiation.
    Objectives
  • To examine the safety of AAV2hAQP1 gene therapy. To see if the drug increases saliva in people whose parotid glands have had radiation.
    Eligibility
  • People at least 18 years of age with a history of radiation therapy for head and neck cancer.
    Design

Participants will be screened in 2 visits with:

  • medical history
  • physical exam
  • scans
  • saliva collections
  • sialogram. A substance is injected in the parotid gland and X-rays are taken.
  • non-drug infusion
  • IV dose of glycopyrrolate to stop saliva

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3-day hospital stay: Participants will get the gene infusion. The AAV2hAQP1 will be in a solution in a syringe. It will be slowly pushed through an opening into the gland inside your mouth.

10 outpatient visits over 3 years. These may include:

  • repeats of screening tests
  • blood and urine tests
  • oral and head and neck exams, including a thin scope in the airway
  • questionnaires
  • small piece of skin taken
  • small piece of parotid tissue taken by either: a small video-scope in the parotid duct that also takes pictures or by a small needle guided by ultrasound
  • scans. Participants lie in a machine or a scanner The machine may feel close to the body or face. . For some, a substance will be injected in a vein or put in the mouth.
  • Participants will keep a diary about how they feel before and after the therapy.
  • oral microbiome gingival and buccal swab

Detailed Study Description

The treatment of most head and neck cancer patients includes ionizing radiation (IR). Salivary glands in the IR field suffer irreversible damage. There is no conventional treatment available to correct this condition. Our research group has been developing an adeno-associated virus vector based on the hypothesis that this vector is capable of safely transferring the human aquaporin-1 (hAQP1) cDNA gene to parotid glands of adult patients with IR-induced salivary hypofunction, resulting in an elevated salivary output. Human AQP1, the archetypal water channel, is a plasma membrane protein that facilitates water movement across lipid bilayers. Minipig studies have shown that the AAV2hAQP1 strategy for restoring salivary flow to IR-damaged salivary glands is effective without untoward effects after salivary gland delivery. As a proof of concept that AQP1 would restore saliva flow in a human population, we recently completed a phase 1 clinical trial (06-D-0206) using an Adenovirus-based vector encoding AQP1 to a single previously irradiated parotid gland in eleven patients using an open label, single dose, dose-escalation design. All patients tolerated vector delivery and study procedures well and positive objective and subjective responses were seen in five patients, all at doses <5.8 times10(9) vp/gland. At higher doses the patients possibly initiated an immune response to the vector and no improvement in gland function was observed. These findings have encouraged us to pursue studies with AAV2 based vectors, which have demonstrated lower immunogenicity and more stable expression compared with adenoviral vectors. The purpose of this clinical protocol is to test the safety of AAV2hAQP1, with some measures of efficacy, in adult patients with established IR-induced parotid gland hypofunction. The targeted tissue site for the AAV2hAQP1 vector in the proposed study is a single parotid gland. In this Phase 1 dose-escalation study, safety will be evaluated using conventional clinical and immunological parameters. The primary outcome measure for biological efficacy will be parotid gland salivary output.

Clinical Study Identifier: NCT02446249

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Recruitment Status: Open


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