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

17 Participants Needed

Trial Summary

What is the purpose of this trial?

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 of the head, neck, and chest * intravenous administration of glycopyrrolate to stop saliva * saliva collections * sialogram which is a procedure in which a substance is injected in the parotid gland and X-rays are taken. * non-drug infusion * a small piece of skin being taken 3-5-day hospital stay: Participants will receive the gene infusion. The AAV2hAQP1 will be in a solution in a syringe. It will be slowly pushed into the parotid gland through the parotid duct, an opening in the mouth near the second upper molar tooth. 10 outpatient visits over 3 years. These may include: * repeats of selected screening tests, including saliva collection * blood and urine tests * oral and dental examinations * head and neck exams, including the use of a thin scope to see the back of the throat * questionnaires * a small piece of parotid tissue being taken by either a small scope through the parotid duct or by a small needle guided by ultrasound * scans of the head and neck. For some, contrast will be injected in a vein * completion of a diary about how the participant feels between visits * swabs of teeth and gums to assess the microbiome of the mouth

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.

What data supports the effectiveness of the treatment AAV2hAQP1 for radiation-induced dry mouth?

Research shows that a similar treatment using the aquaporin-1 gene increased saliva production in both humans and animals with radiation-induced dry mouth. In a study, patients experienced a significant increase in saliva flow and improved symptoms for several years after treatment, with no major side effects. ^{1 2 3 4 5}

Is the gene therapy treatment AAV2hAQP1 safe for humans?

The gene therapy treatment AAV2hAQP1 has been tested in animals and humans, showing no significant adverse effects. Studies in mice, pigs, and monkeys, as well as a clinical trial in humans, reported no major safety concerns, indicating it is generally safe. ^{1 5 6 7 8}

How does the treatment AAV2hAQP1 for radiation-induced dry mouth differ from other treatments?

AAV2hAQP1 is unique because it uses gene therapy to introduce the aquaporin-1 gene into salivary glands, which helps increase saliva production by enhancing water movement in the cells. This approach is different from traditional treatments as it directly targets the underlying cause of dry mouth by restoring gland function, rather than just alleviating symptoms. ^{1 4 5 9 10}

Research Team

John A Chiorini, Ph.D.

Principal Investigator

National Institute of Dental and Craniofacial Research (NIDCR)

Eligibility Criteria

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.

I do not have an active infection requiring IV antibiotics 1 week before starting.

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

Timeline

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Late responses to adenoviral-mediated transfer of the aquaporin-1 gene for radiation-induced salivary hypofunction. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Promising Gene Therapeutics for Salivary Gland Radiotoxicity. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Development of a gene transfer-based treatment for radiation-induced salivary hypofunction. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

In Vivo Transfection of Rat Salivary Glands With Fluorescently Tagged Aquaporin-5 Channel DNA. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Increased fluid secretion after adenoviral-mediated transfer of the human aquaporin-1 cDNA to irradiated miniature pig parotid glands. [2018]

6. United States 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. [2021]

7. England pubmed.ncbi.nlm.nih.gov

AAV2-mediated transfer of the human aquaporin-1 cDNA restores fluid secretion from irradiated miniature pig parotid glands. [2021]

8. England 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. [2006]

9. United States pubmed.ncbi.nlm.nih.gov

Increased fluid secretion after adenoviral-mediated transfer of the aquaporin-1 cDNA to irradiated rat salivary glands. [2023]

10. England 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. [2019]