Gene Therapy for Radiation-Induced Dry Mouth
(AQUAX2 Trial)
Recruiting in Palo Alto (17 mi)
+22 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: MeiraGTx, LLC
Must not be taking: Immunosuppressants
Disqualifiers: Malignancy, Autoimmune disease, Viral infections, others
Prior Safety Data
Approved in 3 Jurisdictions
Trial Summary
What is the purpose of this trial?This trial will test a gene therapy injection into the salivary glands to help adults with severe dry mouth caused by radiation therapy produce more saliva. Gene therapy for dry mouth disorders has moved from theoretical to clinical proof with an initial trial using a specific method to express a protein in patients with radiation-induced dry mouth.
Will I have to stop taking my current medications?
If you are taking a prescription sialagogue (a medication that increases saliva, like pilocarpine or cevimeline), you must stop it at least 2 weeks before the screening and not take it during the study. If you are on other medications that affect saliva, you need to be on a stable dose for at least a month before the screening.
What data supports the effectiveness of the treatment AAV2-hAQP1 for radiation-induced dry mouth?
Research shows that a similar treatment, AdhAQP1, increased saliva flow in both humans and animals with radiation-damaged salivary glands, with some patients experiencing benefits for several years. This suggests that AAV2-hAQP1 might also help improve saliva production in similar conditions.
12345Is the gene therapy treatment AAV2-hAQP1 safe for humans?
Research on a similar treatment, AdhAQP1, showed no significant adverse effects in humans over several years, and animal studies with AAV2-hAQP1 indicated it was safe, with no major health issues observed.
14678How does the treatment AAV2-hAQP1 for radiation-induced dry mouth differ from other treatments?
AAV2-hAQP1 is unique because it uses gene therapy to deliver the human aquaporin-1 (hAQP1) gene directly to the salivary glands, which helps restore fluid secretion by increasing water movement in the cells. This approach is different from traditional treatments as it targets the underlying cause of dry mouth by enhancing the gland's natural ability to produce saliva, rather than just alleviating symptoms.
13469Eligibility Criteria
Adults who've had radiation therapy for head and neck cancer at least 3 years ago, have a certain level of dry mouth severity, and can produce some saliva. They shouldn't have recurring or new cancers, be on specific medications affecting saliva, or have conditions like uncontrolled diabetes, recent smoking history, alcohol misuse, autoimmune diseases affecting salivary glands or certain infections.Inclusion Criteria
Average screening XQ Total Score at or above a specified threshold
I chose to stop or not start prescribed medication for dry mouth.
I don't have head or neck cancer based on recent exams and scans.
+6 more
Exclusion Criteria
I have an autoimmune disease like Sjogren's that affects my salivary glands.
I am currently using or have recently used medication that weakens my immune system.
Evidence of active Hepatitis C virus (HCV) infection
+9 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive bilateral intra-parotid administration of AAV2-hAQP1 or placebo
Single administration
1 visit (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
12 months
Regular visits (frequency not specified)
Participant Groups
The trial is testing two different doses of AAV2-hAQP1 gene therapy against a placebo to see if they can safely improve dry mouth caused by past radiation treatments. Participants will receive the treatment directly into their parotid gland (a major salivary gland).
3Treatment groups
Experimental Treatment
Placebo Group
Group I: AAV2-hAQP1 Group 2Experimental Treatment1 Intervention
Eligible participants will receive up to 3 mL of concentration 1 of AAV2-hAQP1 via Stensen's duct to each parotid gland
Group II: AAV2-hAQP1 Group 1Experimental Treatment1 Intervention
Eligible participants will receive up to 3 mL of concentration 1 of AAV2-hAQP1 via Stensen's duct to each parotid gland
Group III: Placebo groupPlacebo Group1 Intervention
Eligible participants will receive up to 3 mL of diluent via Stensen's duct to each parotid gland
AAV2-hAQP1 is already approved in United States, Canada, United Kingdom for the following indications:
🇺🇸 Approved in United States as AAV2-hAQP1 for:
- Radiation-induced late xerostomia (Grade 2/3)
🇨🇦 Approved in Canada as AAV2-hAQP1 for:
- Radiation-induced late xerostomia (Grade 2/3)
🇬🇧 Approved in United Kingdom as AAV2-hAQP1 for:
- Radiation-induced late xerostomia (Grade 2/3)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
UT Southwestern Medical CenterDallas, TX
University of MissouriColumbia, MO
Sidney Kimmel Comprehensive Cancer CenterBaltimore, MD
Erie County Medical CenterBuffalo, NY
More Trial Locations
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Who Is Running the Clinical Trial?
MeiraGTx, LLCLead Sponsor
References
Late responses to adenoviral-mediated transfer of the aquaporin-1 gene for radiation-induced salivary hypofunction. [2019]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.
Increased fluid secretion after adenoviral-mediated transfer of the human aquaporin-1 cDNA to irradiated miniature pig parotid glands. [2018]The treatment of most head and neck cancer patients includes ionizing radiation (IR). Salivary glands in the IR field suffer irreversible damage. Previously, we reported that adenoviral (Ad)-mediated transfer of the human aquaporin-1 (hAQP1) cDNA to rat submandibular glands following IR restored salivary flow to near normal levels. It is unclear if this strategy is useful in larger animals. Herein, we evaluated AdhAQP1-mediated gene transfer after parotid gland IR (20 Gy) in the miniature pig. Sixteen weeks following IR, salivation from the targeted gland was decreased by >80%. AdhAQP1 administration resulted in a dose-dependent increase in parotid salivary flow to approximately 80% of pre-IR levels on day 3. A control Ad vector was without significant effect. The effective AdhAQP1 dose was 2.5 x 10(5) pfu/microl infusate, a dose that leads to comparable transgene expression in murine and minipig salivary glands. Three days after Ad vector administration little change was observed in clinical chemistry and hematology values. These findings demonstrate that localized delivery of AdhAQP1 to IR-damaged salivary glands increases salivary secretion, without significant general adverse events, in a large animal model.
Transfer of the AQP1 cDNA for the correction of radiation-induced salivary hypofunction. [2016]The treatment of most patients with head and neck cancer includes ionizing radiation (IR). Salivary glands in the IR field suffer significant and irreversible damage, leading to considerable morbidity. Previously, we reported that adenoviral (Ad)-mediated transfer of the human aquaporin-1 (hAQP1) cDNA to rat [C. Delporte, B.C. O'Connell, X. He, H.E. Lancaster, A.C. O'Connell, P. Agre, B.J. Baum, Increased fluid secretion after adenoviral-mediated transfer of the aquaporin-1 cDNA to irradiated rat salivary glands. Proc. Natl. Acad. Sci. U S A. 94 (1997) 3268-3273] and miniature pig [Z. Shan, J. Li, C. Zheng, X. Liu, Z. Fan, C. Zhang, C.M. Goldsmith, R.B. Wellner, B.J Baum, S. Wang. Increased fluid secretion after adenoviral-mediated transfer of the human aquaporin-1 cDNA to irradiated miniature pig parotid glands. Mol. Ther. 11 (2005) 444-451] salivary glands approximately 16 weeks following IR resulted in a dose-dependent increase in salivary flow to > or =80% control levels on day 3. A control Ad vector was without any significant effect on salivary flow. Additionally, after administration of Ad vectors to salivary glands, no significant lasting effects were observed in multiple measured clinical chemistry and hematology values. Taken together, the findings show that localized delivery of AdhAQP1 to IR-damaged salivary glands is useful in transiently increasing salivary secretion in both small and large animal models, without significant general adverse events. Based on these results, we are developing a clinical trial to test if the hAQP1 cDNA transfer strategy will be clinically effective in restoring salivary flow in patients with IR-induced parotid hypofunction.
Persistence of hAQP1 expression in human salivary gland cells following AdhAQP1 transduction is associated with a lack of methylation of hCMV promoter. [2019]In 2012, we reported that 5 out of 11 subjects in a clinical trial (NCT00372320) administering AdhAQP1 to radiation-damaged parotid glands showed increased saliva flow rates and decreased symptoms over the initial 42 days. AdhAQP1 is a first-generation, E1-deleted, replication-defective, serotype 5 adenoviral vector encoding human aquaporin-1 (hAQP1). This vector uses the human cytomegalovirus enhancer/promoter (hCMVp). As subject peak responses were at times much longer (7-42 days) than expected, we hypothesized that the hCMVp may not be methylated in human salivary gland cells to the extent previously observed in rodent salivary gland cells. This hypothesis was supported in human salivary gland primary cultures and human salivary gland cell lines after transduction with AdhAQP1. Importantly, hAQP1 maintained its function in those cells. Conversely, when we transduced mouse and rat cell lines in vitro and submandibular glands in vivo with AdhAQP1, the hCMVp was gradually methylated over time and associated with decreased hAQP1 expression and function in vitro and decreased hAQP1 expression in vivo. These data suggest that the hCMVp in AdhAQP1was probably not methylated in transduced human salivary gland cells of responding subjects, resulting in an unexpectedly longer functional expression of hAQP1.
Safety and efficacy of adenovirus-mediated transfer of the human aquaporin-1 cDNA to irradiated parotid glands of non-human primates. [2006]This study evaluated the safety and efficacy of a single administration of a recombinant adenovirus encoding human aquaporin-1 (AdhAQP1) to the parotid glands of adult rhesus monkeys. In anticipation of possible clinical use of this virus to correct irradiation damage to salivary glands, AdhAQP1 was administered (at either 2 x 10(9) or 1 x 10(8) plaque-forming units/gland) intraductally to irradiated glands and to their contralateral nonirradiated glands. Radiation (single dose, 10 Gy) significantly reduced salivary flow in exposed glands. Virus administration resulted in gene transfer to irradiated and nonirradiated glands and was without untoward local (salivary) or systemic (sera chemistry, complete blood count) effects in all animals. However, the effect of AdhAQP1 administration varied and did not result in a consistent positive effect on salivary flow rates for all animals under these experimental conditions. We conclude that a single adenoviral-mediated gene transfer to primate salivary glands is well-tolerated, although its functional utility in enhancing fluid secretion from irradiated parotid glands is inconsistent.
Increased fluid secretion after adenoviral-mediated transfer of the aquaporin-1 cDNA to irradiated rat salivary glands. [2023]A replication-deficient, recombinant adenovirus encoding human aquaporin-1 (hAQP1), the archetypal water channel, was constructed. This virus, AdhAQP1, directed hAQP1 expression in several epithelial cell lines in vitro. In polarized MDCK cell monolayers, hAQP1 was localized in the apical and basolateral plasma membranes. Fluid movement across monolayers infected by AdhAQP1 in response to an osmotic gradient was approximately 4-fold that seen with uninfected monolayers or monolayers infected by a control virus. When AdhAQP1 was administered to rat submandibular glands by retrograde ductal instillation, significant hAQP1 expression was observed by Western blot analysis in crude plasma membranes and by immunohistochemical staining in both acinar and ductal cells. Three or four months after exposure to a single radiation dose (17.5 or 21 Gy, respectively), AdhAQP1 administration to rat submandibular glands led to a two- to threefold increase in salivary secretion compared with secretion from glands administered a control virus. These results suggest that hAQP1 gene transfer may have potential as an unique approach for the treatment of postradiation salivary hypofunction.
Transient detection of E1-containing adenovirus in saliva after the delivery of a first-generation adenoviral vector to human parotid gland. [2021]Radiation-induced salivary hypofunction is a common side-effect of treatment for head and neck cancers. Patients suffer significant morbidity and there is no suitable conventional therapy. We are conducting a Phase I clinical trial, using a first-generation serotype 5 adenoviral (Ad5) vector encoding human aquaporin-1 (AdhAQP1) to treat such patients. One week after the administration of AdhAQP1 to an enrolled, generally healthy patient, E1-containing adenovirus was detected in parotid saliva.
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]In preparation for testing the safety of using serotype 2 recombinant adeno-associated vector, encoding Aquaporin-1 to treat radiation-induced salivary gland damage in a phase 1 clinical trial, we conducted a 13 week GLP biodistribution and toxicology study using Balb/c mice. To best assess the safety of rAAV2hAQP1 as well as resemble clinical delivery, vector (10(8), 10(9), 10(10), or 4.4 × 10(10) vector particles/gland) or saline was delivered to the right parotid gland of mice via retroductal cannulation. Very mild surgically induced inflammation was caused by this procedure, seen in 3.6% of animals for the right parotid gland, and 5.3% for the left parotid gland. Long term distribution of vector appeared to be localized to the site of cannulation as well as the right and left draining submandibular lymph nodes at levels >50 copies/μg in some animals. As expected, there was a dose-related increase in neutralizing antibodies produced by day 29. Overall, animals appeared to thrive, with no differences in mean body weight, food or water consumption between groups. There were no significant adverse effects due to treatment noted by clinical chemistry and pathology evaluations. Hematology assessment of serum demonstrated very limited changes to the white blood cell, segmented neutrophils, and hematocrit levels and were concluded to not be vector-associated. Indicators for liver, kidney, cardiac functions and general tissue damage showed no changes due to treatment. All of these indicators suggest the treatment is clinically safe.
AAV2-mediated transfer of the human aquaporin-1 cDNA restores fluid secretion from irradiated miniature pig parotid glands. [2021]Previously (Shan et al, 2005), we reported that adenoviral vector-mediated transfer of the human aquaporin-1 (hAQP1) cDNA to minipig parotid glands following irradiation (IR) transiently restored salivary flow to near normal levels. This study evaluated a serotype 2, adeno-associated viral (AAV2) vector for extended correction of IR (single dose; 20 Gy)-induced, parotid salivary hypofunction in minipigs. At 16 weeks following the IR parotid salivary flow decreased by 85-90%. AAV2hAQP1 administration at week 17 transduced only duct cells and resulted in a dose-dependent increase in salivary flow to approximately 35% of pre-IR levels (to approximately 1 ml per 10 min) after 8 weeks (peak response). Administration of a control AAV2 vector or saline was without effect. Little change was observed in clinical chemistry and hematology values after AAV2hAQP1 delivery. Vector-treated animals generated high anti-AAV2 neutralizing antibody titers by week 4 (approximately 1:1600) and significant elevations in salivary (approximately 15%), but not serum, granulocyte macrophage colony-stimulating factor levels. Following vector administration, salivary [Na(+)] was dramatically increased, from approximately 10 to approximately 55 mM (at 4 weeks) and finally to 39 mM (8 weeks). The findings demonstrate that localized delivery of AAV2hAQP1 to IR-damaged parotid glands leads to increased fluid secretion from surviving duct cells, and may be useful in providing extended relief of salivary hypofunction in previously irradiated patients.