MGTX - MeiraGTx Announces an Oral Presentation and Eight Posters at the European Society of Gene and Cell Therapy (ESGCT) 2023 Annual Congress | Benzinga
LONDON and NEW YORK, Oct. 24, 2023 (GLOBE NEWSWIRE) -- MeiraGTx Holdings plc (NASDAQ:MGTX), a vertically integrated, clinical stage gene therapy company, today announced the Company will exhibit eight posters and deliver one oral presentation at the European Society of Gene and Cell Therapy (ESGCT) 2023 Annual Congress, which is being held from October 24-27, 2023, in Brussels, Belgium.
"The number of acceptances for presentation at this year's ESGCT congress underscores our commitment to remain at the forefront of genetic medicine by developing a new generation of therapies for multiple indications, including xerostomia and ALS," said Alexandria Forbes, Ph.D., president and chief executive officer of MeiraGTx. "The collective data presented provide further clinical and preclinical validation of our platform and reflect the progress we continue to make, particularly in riboswitch and neurodegenerative programs. We look forward to sharing data at ESGCT highlighting our innovative pipeline, manufacturing, and R&D capabilities."
The posters will be available on the Posters and Publications page of the Company's website.
The details of the oral and poster presentations are below:
Oral Presentation OR82: Preclinical Efficacy of AAV-hUPF1 with an optimized vector genome and novel CNS capsid: Gene Therapy for ALS and FTD
Friday, October 27th at 11:00-13:00 CEST in Shed 2B (3rd talk)
Session 11b: CNS and Sensory Disease III
ALS is a progressive neurodegenerative disease that affects neurons in the brain and spinal cord. Here, we present preclinical efficacy of AAV-hUPF1 in multiple models of ALS. hUPF1 is an RNA helicase that regulates NMD that we have optimized for AAV gene therapy of ALS.
At 4.9 kb, the optimized hUPF1 construct is 1.5 kb smaller than the original, thus offering AAV packaging and manufacturing benefits while demonstrating greater efficacy. When tested in vitro, the optimized AAV-hUPF1 rescued toxicity in both the TDP-43 and C9orf72 iNeurons models, at lower MOIs than the original. Optimized AAV-hUPF1 also rescued the pathophysiology of neurons derived from C9orf72 patient cell lines. Transduction in C9 patient-derived neurons indicated target engagement with down-regulation of C9 intron containing transcripts and known NMD targets. AAV-hUPF1 also showed in vivo efficacy in FUS transgenic mouse. Transduction of ~36% of spinal neurons was sufficient to drive significant rescue with surviving motor neuron count comparable to WT level.
Furthermore, we developed a novel AAV capsid that expresses in neurons of both the brain and spinal cord when administered by ICM in mice. This ideal pattern was confirmed in NHPs with transduction that achieved levels sufficient to provide functional rescue in an in vivo model. The prospect of an efficient capsid for CNS delivery is aligned with our therapeutic goal of minimizing AAV exposure while maintaining strong transduction. Together, the evidence in in vitro and in vivo with TDP-43, C9orf72, and FUS models suggests that hUPF1 delivered by MeiraGTx vector is agnostic to genetic background and shows promise in treating ALS.
Poster #008: Results of a phase 1 open-label, dose escalation study of gene therapy with AAV2-hAQP1 as treatment for radiation-induced xerostomia and parotid gland hypofunction
Category: AAV & non integrative vectors
In radiation-induced xerostomia, the normal architecture and function of salivary glands are significantly disrupted or destroyed. AAV2-hAQP1 vector expresses the human Aquaporin 1 (hAQP1) gene delivered using the AAV2 capsid. When hAQP1 is expressed in cells of the disrupted glands, the cells become permeable to water. Water flows down the hydrostatic pressure gradient through the salivary duct and into the mouth.
In this study AAV2-hAQP1, at doses ranging from 1 × 1011 vg/gland to 3 × 1012 vg/gland, was administered to one (unilateral) or both (bilateral) parotid glands via intraoral, retroductal cannulation of Stensen's duct. Key inclusion criteria for study participants were a history of head and neck cancer, a minimum of 5 years since final radiotherapy treatment (2+ years if HPV+), the presence of grade 2/3 late xerostomia, no evidence of cancer recurrence or second primary, and abnormal parotid gland function. Key exclusion criteria were a history of autoimmune disease affecting the salivary glands and a hemoglobin A1c greater than 7%.
Safety parameters included assessments of adverse events, physical examination observations, clinical laboratory results, and electrocardiogram findings. Efficacy assessments included participant completion of the Xerostomia-specific Questionnaire (XQ) and Global Rate of Change Questionnaire (GRCQ). The XQ is a patient reported outcome measure consisting of 8 symptom-specific questions the participant rates from 0 (not present) to 10 (worst possible). The sum of all ratings (0-80) provides an overall measure of symptom burden. The GRCQ is a patient reported outcome tool that has been adapted for xerostomia. The GRCQ first asks the participant if their dry mouth is "better", "worse", or "about the same" following treatment. If the participant reports "better" or "worse," they are then asked to rate the degree of change on a scale from 1 to 7, with 1 being the smallest change and 7 being the greatest change. A score of 2 or above is important to the patient. To evaluate the biologic activity of AAV2-hAQP1, the change from baseline to Month 12 in whole saliva flow rate was assessed.
A total of 24 adults were enrolled in the study, with twelve participants treated unilaterally and twelve treated bilaterally. AAV2-hAQP1 was safe and well-tolerated at all dose levels, with no treatment-related serious adverse events or dose limiting toxicity.
At Month 12, 16 of the 24 participants had an improvement of ?8 points in XQ score, and 18 of the 24 reported important improvement in xerostomia symptoms relative to baseline on the GRCQ. In bilaterally treated participants, the average percent increase in unstimulated whole saliva flow rate at Month 12 post-treatment relative to baseline was 82.1%. On all efficacy measures, greater improvement was observed in bilaterally treated participants than in those treated unilaterally.
Poster #116: fDISCO evaluation of AAV mediated gene expression upon different routes of administration
Category: AAV & non integrative vectors
Detection methods to assess gene transfer mediated expression of reporter proteins in tissue requires to dissect or slice the sample, during which the three-dimensional (3D) structure is lost. On the other hand, live imaging often does not provide enough resolution to identify reporter protein expression on a cellular level. Here, we have tested whether fDISCO (3D imaging of solvent-cleared organs with superior fluorescence-preserving capability) could overcome these limitations. To this end, DBA/1 mice were injected intraarticularly (IA), intramuscularly (IM), or intravenously (IV) with AAV encoding fluorochrome mGreenLantern (mGL). Hindlimbs and livers were isolated three weeks after administration, followed by fDISCO tissue clearing. Cleared tissues were imaged by a light-sheet fluorescence microscope, followed by image stitching to create the 3D structure of ...