MeiraGTx Announces the Presentation of Two Novel Inherited Retinal Disease (IRD) Programs and Riboswitch Gene Regulation Platform

MeiraGTx announced three poster presentations at the European Society of Gene and Cell Therapy (ESGCT) 2021 Annual Congress. Two preclinical programs addressing inherited retinal diseases (IRDs) caused by mutations in KCNV2 and GUCY2D are presented with data supporting the development of these viral vectors as gene therapies.

A third presentation outlines MeiraGTx’s proprietary gene regulation platform demonstrating tight regulation of gene expression to high dynamic range in mammalian cells and precise regulation in vivo in response to dosing of an oral small molecule.

“We’re pleased to present data illustrating the depth and versatility of our scientific platform, including early data on optimized viral vectors for two Inherited Retinal Diseases, as well initial data from our novel gene regulation platform,” Alexandria Forbes, PhD, President and Chief Executive Officer of MeiraGTx, said in a company news release. “Since our formation more than 6 years ago, in addition to developing novel vectors for gene replacement therapies in inherited diseases such as IRDs, we have aimed to develop gene regulation technology that may be applied to larger more common diseases. The company’s synthetic riboswitch gene regulation system provides an unprecedented platform for spatial and temporal control of gene therapy with broad implications for the applicability of genetic medicines for treating a wide range of potential disorders not limited to inherited diseases. We look forward to discussing our riboswitch gene regulation platform in more detail at an R&D Day later this year.”

MeiraGTx continues to anticipate up to two new INDs for novel viral vectors addressing IRDs in 2022.

The company will hold a research and development day in December 2021 in which further data on its synthetic riboswitch gene regulation platform as well as the Company’s proprietary promoter platforms will be presented.

ESGCT 2021 Presentations and Data Summaries:

Title: Novel riboswitches regulate AAV delivered transgene expression in mammals via small molecule inducers
Poster ID: P164
Presenter: A. J. Forbes
Date and Time: Tuesday, October 19, 8:00 am CEST (2:00 am ET)
Session: Gene Targeting

As the field of gene therapy has progressed, multiple elements of viral vectors have been optimized to increase potency, specificity and safety of these therapies including the development of engineered promoters and transcriptional regulatory elements. However, until now the development of tight temporal control of gene therapies using oral small molecules has remained elusive, and protein-based switches have proved of little use due to low dynamic range, low levels of expression, and potential for immunogenicity.

MeiraGTx presents a potent gene regulation platform based on rationally designed synthetic riboswitches built in mammalian cells. These riboswitches drive a splicing-based expression platform engineered to create an ‘on’ switch in the presence of specific aptamer small molecule binding. Small molecule binding results in hairpin stabilization sequestering a splice site of an alternative exon. This platform regulates protein expression with high dynamic range and allows precise control of transgene expression levels. The extremely high dynamic range of this switch has allowed us to screen, identify and modify novel aptamers that bind and respond to novel small molecules. This platform is modular and adjustable and is optimized for each transgene to achieve the required expression level and dynamic range. This regulation platform has been demonstrated to work in multiple genes, multiple cell types in vitro and in vivo. When delivered through an AAV vector in mice, the engineered riboswitches reversibly regulate transgene expression via an orally delivered small molecule inducer, providing precise control of transgene expression. MeiraGTx’s potent gene regulation system provides a platform for using unique aptamer-ligand pairs to regulate genes in mammals.

• Rationally designed synthetic riboswitches activate transgene expression via a splicing based expression platform cassette
• Novel synthetic riboswitches are highly dynamic in regulating gene expression in mammalian cells allowing precise activation of gene expression with small molecule inducers
• Aptamers are interchangeable within the switch and multiple novel synthetic aptamer and novel small molecule pairs have been generated
• Multiple transgenes have been regulated in multiple cell types in vitro and in vivo
• AAV delivered transgene expression is precisely regulated in a dose-dependent fashion in vivo via orally available small molecule inducer

This platform enables precise temporal and spatial control of gene expression, expanding the range of possibilities for using gene-based vectors as therapies.

Title: KCNV2 retinal organoid disease model for KCNV2 AAV gene therapy development
Poster ID: P364
Presenter: S. Ferrara
Date and Time: Tuesday, October 19, 8:00 am CEST (2:00 am ET)
Session: Stem Cells & Regenerative Medicine

Assessment of potential AAV gene replacement therapies for KCNV2 mutations demonstrates that AAV-KCNV2-mediated gene therapy is a promising approach to the treatment of patients with cone-dystrophy due to KCNV2mutations. CRISPR/Cas9 gene editing was used to generate human KCNV2 Knockout (KCNV2 KO) and isogenic human control retinal organoids. KCNV2 KO retinal organoids were used to screen eight AAV vectors containing expression cassettes coding for either WT or codon-optimized versions of hKCNV2, as driven by either constitutive (CAG) or photoreceptor-specific rhodopsin kinase (RK) promoters. Both AAV5 and AAV7m8 vectors were assessed for their ability to restore hKCNV2 RNA expression and Kv8.2 localization to the inner segment of rod and cone photoreceptor cells following transduction.

All vectors tested successfully delivered the hKCNV2 gene to photoreceptors in retinal organoids following transduction, restoring protein expression in the correct subcellular location as well as native protein-to-protein interactions. Transcriptomic analyses (single-cell RNA) indicated disease correction at a deep transcriptional level, and that AAV-mediated KCNV2 gene supplementation has the potential to benefit patients with cone dystrophies due to KCNV2 mutations.

Title: GUCY2D retinal organoid disease model for AAV gene therapy development
Poster ID: P395
Presenter: A. Naeem
Date and Time: Tuesday, October 19, 8:00 am CEST (2:00 am ET)
Session: Stem Cells & Regenerative Medicine

Assessment of potential AAV gene replacement therapies for GUCY2D mutations demonstrates that AAV-GUCY2D gene therapy constitutes a promising treatment for patients with cone-rod dystrophy due to GUCY2Dmutations. Four AAV vectors, packaged into 7m8 capsids, were designed to enable the restoration of GUCY2D-mediated signaling in photoreceptor outer segments via gene replacement. Transduction of GUCY2D Knockout (GUCY2D KO) human retinal organoids by all vectors improved quantitative expression levels of GUCY2D and PDE6β relative to non-transduced controls, and total cGMP levels in transduced GUCY2D KO human retinal organoids were restored to close to those observed in healthy human retinal organoids, demonstrating vector potency and transgene function. These results indicate that gene replacement in GUCY2D-deficient human retinal organoids restored protein expression and cGMP levels in transduced organoids. This provides support for the potential use of AAV-mediated GUCY2D gene supplementation as a treatment for patients with inherited retinal dystrophy caused by mutations in GUCY2D.