MeiraGTx Announces Five Posters at the European Society of Gene and Cell Therapy (ESGCT) 2024 Annual Congress

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Multiple Posters Highlight the Breadth of Company’s Novel Genetic Medicine and Cell Therapy Platforms LONDON and NEW YORK, Oct. 22, 2024 (GLOBE NEWSWIRE) -- MeiraGTx Holdings plc (Nasdaq: MGTX), a vertically integrated, clinical-stage genetic medicines company, today announced the Company will exhibit five posters at the European Society of Gene and Cell Therapy (ESGCT) 2024 Annual Congress, which is being held from October 22-25, 2024 , in Rome, Italy . The posters are available on the Posters and Publications page of the Company’s website. The details of the poster presentations are as follows: Poster Number: P0015 Abstract Title: Evolution of a high-producing, modular upstream platform for AAV manufacturing Poster Session III: Tuesday 22 October from 19:30 to 21:00 CEST Abstract: The poster shows the evolution of MeiraGTx’s upstream manufacturing platform, which was optimized and modulated through the choice of transfection reagents, adeno-associated virus (AAV) production enhancers, and transfection parameters, in fed-batch and perfusion culture mode. Over 3 years, we have achieved process optimizations yielding AAV titers up to 1x1012 VG/mL at harvest and >40% full capsids prior to polishing purification steps. Product quality attributes such as encapsidated residual plasmid DNA and host cell DNA are demonstrated to be controllable and maintained to satisfactory levels for patient safety through the combination of transfection reagent, small molecule enhancer, and transfection mix formulation parameters. Operating a perfusion-based process has also increased volumetric VG yield by approximately 40% and reduced plasmid DNA usage by at least 25%, without compromising on AAV productivity and product quality, demonstrating additional cost savings. Poster Number: P0020 Abstract Title: AAV-based evaluation of novel in silico promoters to drive expression in rod photoreceptors Poster Session II: Wednesday 23 October from 13:30 to 15:00 CEST Abstract: As rods outnumber cones by a ratio of 1:20 or greater in the retina and defects are common in rods leading to various ocular diseases, we sought to design and test novel promoters to drive expression specifically and at high expression levels in rods. Using an AI-assisted promoter engineering approach, ten novel promoter sequences were initially designed, cloned into an adeno-associated virus (AAV) backbone carrying eGFP and finally packaged into AAV5 or AAV7m8. In addition, AAV5 and AAV7m8 vectors were produced carrying the commonly used rhodopsin kinase (RK) promoter and eGFP. Following the initial screen, five second-generation, improved promoter sequences were designed combining elements from preferred performers of the first screen and again packaged into AAV5 and AAV7m8 for additional analysis. Wild-type mice received subretinal injections with the AAV5 vectors to assess promoter activity in the murine retina. Four weeks post vector administration, eyes were harvested for immunohistochemical analysis and qPCR expression analysis to determine specificity and expression levels, respectively. In parallel, the AAV7m8 vectors were used to assess promoter activity in human pluripotent stem cell (hPSC)-derived retinal organoids. Three weeks post-transduction, organoids were fixed and dissociated into single cells for FACS analysis or cryosectioned for immunohistochemistry. Sections were stained with markers of rod and cone photoreceptors and quantitatively assessed for eGFP co-expression. Lead candidates were identified based on promoter specificity to rod photoreceptors, determined by immunohistochemistry, and promoter strength, measuring expression level using qPCR or signal intensity using FACS. Poster Number: P0129 Abstract Title: Identification of highly potent and tissue-specific promoters with massively parallel screening Poster Session III: Tuesday 22 October from 19:30 to 21:00 CEST Abstract: Promoters are an integral component of any effective gene therapy. A potent promoter may allow for a therapeutic effect with a lower dosage, which could lower immune responses and manufacturing costs. A short promoter leaves more space for the transgene and mitigates the cargo capacity constraints of current gene therapy delivery methods. In addition, shorter promoters are especially useful for central nervous system applications as neuronal genes tend to have a longer coding region compared to non-neuronal genes. Here, we developed a massively parallel reporter assay (MPRA) to screen a synthetic library of over 240,000 promoters that are 182 bp long. This flexible AAV-based platform can be applied to diverse model systems including primary human tissue, iPSC-derived organoids, and non-human primates. Initial screening in transfected mouse Neuro2A cells identified hundreds of potent promoter candidates, of which 34 were selected for independent validation using flow cytometry. We identified 15 promoters exhibiting folds higher expression than CAG despite a 10-fold reduction in size in Neuro2A cells. Furthermore, 5 of these promoters are stronger than CMV and 3-fold smaller. In the human Huh7 cell line, all 15 promoters have lower expression than CAG indicating their specificity. In parallel, potent promoters were identified by this platform in human myotubes, primary mouse neurons, mouse liver, and the mouse gastrocnemius muscle. Independent validation of single candidates confirms the strength of our candidate promoters in vivo . These selected promoters can be further engineered using machine learning coupled with rational design to increase promoter potency. This approach allows the screening of hundreds of thousands of rationally designed small promoters (

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