Gene Therapy for Radiation-Induced Dry Mouth

Overseen By Katherine Hall, R.N., MSN

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: MeiraGTx, LLC

Must not be taking: Corticosteroids, Immunosuppressives

Disqualifiers: Pregnancy, Respiratory infections, Heart disease, Autoimmune diseases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 13

Duration: 3-5 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy to help those suffering from dry mouth due to radiation treatment. Researchers are examining a drug called AAV2hAQP1 to assess its safety and ability to boost saliva production in affected individuals. It suits those who have undergone radiation therapy for head and neck cancer and experience dry mouth issues. Participants will receive the treatment in a hospital setting and attend follow-up visits over three years to monitor progress. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial requires that you have been on stable medications for at least 2 months before the gene therapy is administered. If you are on systemic immunosuppressive medications, you may need to stop those, as they are not allowed in the trial.

Is there any evidence suggesting that AAV2hAQP1 gene therapy is likely to be safe for humans?

Research has shown that AAV2hAQP1 gene therapy has been generally safe and well-tolerated in earlier studies. Participants experienced significant relief from dry mouth symptoms. The treatment was tested at different doses, all of which proved safe. No serious side effects were linked to the therapy. This gene therapy remains in the early stages of testing, so researchers are monitoring it closely for safety. Prospective participants might find this information reassuring regarding the treatment's safety. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about AAV2hAQP1 because it offers a novel approach to treating radiation-induced dry mouth. Unlike current treatments, which often focus on symptom relief through saliva substitutes or medications like pilocarpine, AAV2hAQP1 uses gene therapy to address the root cause. This treatment delivers the human aquaporin-1 gene directly into the salivary glands, aiming to restore their natural function and increase saliva production. This innovative mechanism of action has the potential to provide long-term relief, rather than just temporary symptom management.

What evidence suggests that this gene therapy could be effective for radiation-induced dry mouth?

Research has shown that AAV2hAQP1 gene therapy could help treat dry mouth caused by radiation. Studies have found this treatment to be safe and free of harmful effects at the tested doses. Patients who received AAV2hAQP1 experienced significant improvements in their dry mouth symptoms. The therapy adds the aquaporin-1 gene to the salivary glands, enabling them to produce more saliva. This increase in saliva can help prevent issues like infections and tooth decay associated with dry mouth. ^{1 3 4 6 7}

Who Is on the Research Team?

John A Chiorini, Ph.D.

Principal Investigator

National Institute of Dental and Craniofacial Research (NIDCR)

Are You a Good Fit for This Trial?

Adults who've had radiation therapy for head and neck cancer, resulting in dry mouth due to low saliva production from the parotid gland. They must be disease-free for at least 5 years (or 2 years if they had HPV positive oropharyngeal cancer), able to use barrier contraception, have no severe dental issues or allergies related to the trial, not smoke, and can stay in the hospital for 3-5 days.

Inclusion Criteria

Abnormal parotid gland function as judged by both absence of unstimulated parotid salivary flow and a stimulated parotid salivary flow in the targeted parotid gland >0 and <0.3 mL/min/gland after 2% citrate stimulation

My ENT doctor found no signs of my cancer coming back.

I had HPV positive throat cancer and finished my treatment over 2 years ago.

Exclusion Criteria

I have an autoimmune disease like Sjogren's, lupus, or type I diabetes that is stable.

ALT and/or AST > 1.5 times upper limit of normal (ULN) or alkaline phosphatase >1.5 times ULN

Serum creatinine > 2 mg/dL

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2 visits

2 visits (in-person)

Treatment

Participants receive a single administration of AAV2hAQP1 gene therapy to the parotid gland during a 3-5 day hospital stay

3-5 days

1 hospital stay

Follow-up

Participants are monitored for safety and effectiveness after treatment with 10 outpatient visits over 3 years

3 years

10 visits (outpatient)

What Are the Treatments Tested in This Trial?

Interventions

• AAV2hAQP1

Trial Overview The safety of AAV2hAQP1 gene therapy is being tested. This involves a one-time infusion into one parotid salivary gland through the mouth. The goal is to see if this treatment can increase saliva production in those affected by dry mouth after radiation therapy.

How Is the Trial Designed?

Group I: single arm dose escalation Experimental Treatment 1 Intervention

single arm dose escalation

Who Is Running the Clinical Trial?

MeiraGTx, LLC

Lead Sponsor

Trials

6

Recruited

310+

MeiraGTx UK II Ltd

Lead Sponsor

Trials

15

Recruited

710+

National Institute of Dental and Craniofacial Research (NIDCR)

Collaborator

Trials

312

Recruited

853,000+

Published Research Related to This Trial

A 13-week safety study in Balb/c mice showed that the recombinant adeno-associated vector (rAAV2hAQP1) used to treat radiation-induced salivary gland damage was clinically safe, with no significant adverse effects observed in body weight, food or water consumption, and clinical chemistry evaluations.

The treatment resulted in only mild inflammation at the injection site and localized vector distribution, with no significant changes in liver, kidney, or cardiac function, indicating a favorable safety profile for future clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity and biodistribution of the serotype 2 recombinant adeno-associated viral vector, encoding Aquaporin-1, after retroductal delivery to a single mouse parotid gland. Momot, D., Zheng, C., Yin, H., et al.[2021]

The study demonstrated that administering a recombinant adenovirus encoding human aquaporin-1 (AdhAQP1) to the parotid glands of adult rhesus monkeys is safe, with no adverse local or systemic effects observed after treatment.

While the gene transfer was successful in both irradiated and nonirradiated glands, the impact on improving salivary flow rates was inconsistent, indicating that while the treatment is well-tolerated, its effectiveness in enhancing salivary secretion after radiation damage varies among individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of adenovirus-mediated transfer of the human aquaporin-1 cDNA to irradiated parotid glands of non-human primates. O'Connell, AC., Baccaglini, L., Fox, PC., et al.[2006]

A single dose of AAV2hAQP1 delivered to irradiated parotid glands in minipigs significantly increased salivary flow to about 35% of pre-irradiation levels, demonstrating its efficacy in treating salivary hypofunction.

The treatment was safe, with minimal changes in clinical chemistry and hematology, and it effectively targeted duct cells, suggesting potential for extended relief in patients with similar radiation-induced salivary issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV2-mediated transfer of the human aquaporin-1 cDNA restores fluid secretion from irradiated miniature pig parotid glands. Gao, R., Yan, X., Zheng, C., et al.[2021]

The recombinant adenovirus AdhAQP1 effectively increased the expression of human aquaporin-1 in epithelial cells, leading to a fourfold increase in fluid movement across cell monolayers compared to controls.

In a rat model, administering AdhAQP1 to submandibular glands after radiation treatment resulted in a two- to threefold increase in salivary secretion, suggesting its potential as a treatment for postradiation salivary hypofunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased fluid secretion after adenoviral-mediated transfer of the aquaporin-1 cDNA to irradiated rat salivary glands. Delporte, C., O'Connell, BC., He, X., et al.[2023]

In a clinical trial involving 11 subjects, the adenoviral vector AdhAQP1 significantly improved saliva flow rates and reduced symptoms in patients with radiation-damaged parotid glands, with effects lasting longer than expected (7-42 days).

The study suggests that the human cytomegalovirus promoter/enhancer (hCMVp) in AdhAQP1 remains unmethylated in human salivary gland cells, allowing for prolonged expression and function of the human aquaporin-1 protein, unlike in rodent models where methylation led to decreased expression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Persistence of hAQP1 expression in human salivary gland cells following AdhAQP1 transduction is associated with a lack of methylation of hCMV promoter. Zheng, C., Baum, BJ., Liu, X., et al.[2019]

In a clinical trial involving five subjects, administration of the AdhAQP1 gene therapy for radiation-induced salivary hypofunction resulted in significant long-term increases in parotid salivary flow (71-500% above baseline) lasting 3-4.7 years after treatment.

There were no clinically significant adverse events reported, indicating that AdhAQP1 is a safe intervention, and the benefits of the treatment persisted much longer than typically expected from first-generation adenoviral vectors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Late responses to adenoviral-mediated transfer of the aquaporin-1 gene for radiation-induced salivary hypofunction. Alevizos, I., Zheng, C., Cotrim, AP., et al.[2019]

In a study involving miniature pigs, the administration of an adenoviral vector carrying the human aquaporin-1 (hAQP1) gene significantly restored salivary flow in parotid glands damaged by ionizing radiation, achieving about 80% of normal levels within three days.

The treatment was safe, showing no significant adverse effects on clinical chemistry or hematology, indicating that localized gene therapy could be a promising approach for managing radiation-induced salivary gland damage in larger animals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased fluid secretion after adenoviral-mediated transfer of the human aquaporin-1 cDNA to irradiated miniature pig parotid glands. Shan, Z., Li, J., Zheng, C., et al.[2018]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT02446249

Safety of a Single Administration of AAV2hAQP1, an Adeno ... - 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 ...

2. investors.meiragtx.com investors.meiragtx.com/news-releases/news-release-details/meiragtx-announces-positive-clinical-data-aquax-phase-1-clinical

MeiraGTx Announces Positive Clinical Data from the AQUAx ... Positive clinical data from the ongoing Phase 1 AQUAx study of AAV2-hAQP1 for the treatment of grade 2/3 radiation-induced xerostomia (RIX).

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S2212440324006400

Results of a phase 1, open-label, dose-escalation study of ... Treatment with AAV2-hAQP1 was safe and well-tolerated at all doses and resulted in meaningful improvements in xerostomia symptoms and unstimulated whole saliva ...

4. meiragtx.gcs-web.com meiragtx.gcs-web.com/static-files/da32598a-54de-495d-92c4-9c2d9980a03b

Gene Therapy for the Treatment of Radiation-Induced ... ❖ Xerostomia: Subjective feeling of dry mouth – assessed using patient reported outcome measures. (PROs). ❖ Relationship between Xerostomia ...

5. withpower.com withpower.com/trial/phase-1-xerostomia-4-2015-9b8d8

Gene Therapy for Radiation-Induced Dry Mouth AAV2hAQP1 is unique because it uses gene therapy to introduce the aquaporin-1 gene into salivary glands, which helps increase saliva production by enhancing ...

6. investors.meiragtx.com investors.meiragtx.com/static-files/41490406-a3e7-4924-8a9d-9c289d8c4780

Results of a Phase 1, Open-label, Dose-escalation Study of ... with AAV2-hAQP1 as Treatment for Grade 2 and 3 Radiation-induced Late ... Average Dry Mouth score improved by 2.7 points (42.2%) at Month ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05926765

A Study of AAV2-hAQP1 Gene Therapy in Participants With ... This study will assess the efficacy and safety of bilateral intra-parotid administration of AAV2-hAQP1 in adults with Grade 2 or Grade 3 radiation-induced ...