Gene therapy has a reputation as a one-time intervention that has a lifelong effect. It’s an all-or-nothing proposition. But what if it wasn’t? What if gene therapy could be dialed up or down, on a daily basis, with a simple pill? The possibility has inspired MeiraGTx to develop a riboswitch technology that is designed to allow for the precise, dose-responsive control of gene expression by oral small molecules.

The riboswitch technology is just part of MeiraGTx’s work in gene therapy. The company has technologies for the optimization of adeno-associated virus (AAV) vectors and for the design of promoter sequences. Also, the company has an internally developed manufacturing platform process and several production facilities. Finally, the company has several gene therapy programs in late-stage clinical trials.

In recent months, MeiraGTx has reported several business successes. For example, the company entered into a $415 million asset purchase agreement with Janssen Pharmaceuticals related to botaretigene sparoparvovec (bota-vec) for the treatment of X-linked retinitis pigmentosa. MeiraGTx has yet to turn a profit, but the company has a cash runway that should support operations well into 2026.

Capsid/promoter optimization

Alexandria Forbes, PhD
Alexandria Forbes, PhD, CEO, MeiraGTx

The degree of vector optimization at MeiraGTx differentiates it from other gene therapy developers. Its gene therapy platform, which optimizes capsids and promoters, has resulted in extensive, proprietary libraries that contain capsids with increased tropism to different tissues, and that enable insights into promoters and how specific genes are expressed in particular cells.

By making minute changes in capsids, the company can affect gene delivery efficiency. Likewise, by optimizing promoters, the company’s scientists can affect expression levels. For example, they can limit expression to certain cell types.

AI-driven in silico cloning, which the company initiated a few years ago, enhances those results by helping to identify “small, strong, and specific promoters and control elements,” says Alexandria “Zandy” Forbes, PhD, MeiraGTx’s CEO.

Forbes asserts that the resulting libraries enable MeiraGTx to optimize any viral vector, making it up to three logs better than the original. The company makes a point of testing its capsids and promoters in organoids derived from human stem cells to ensure that the vectors are optimized for human potency.

A broad pipeline

MeiraGTx developed its pipeline through partnerships and in-licensing rights from third parties “in an indication-agnostic fashion,” Forbes relates. Initially, the company focused on products for the eye, collaborating with Moorfields Eye Hospital in London and University College London (UCL). “UCL has a very strong retinal organoid group,” Forbes observes. Technology developed by a UCL spinout company, Athena Vision, has become part of MeiraGTx’s ocular program.

“The resulting gene therapy for X-linked retinitis pigmentosa was the one of the first products we tested in human retinal organoids made from stem cells of actual patients who are blind,” Forbes says. “It made the cells function as if the mutation wasn’t there.” It recently completed Phase III trials.

MeiraGTx has also focused on developing immunogenic therapies that needn’t be administered in massive, systemic doses. The company believes that local delivery could allow very small doses to change tissue function or, in the case of Parkinson’s disease, rewire the brain, thus minimizing safety concerns and lowering the cost of goods.

Late-stage clinical programs at MeiraGTx include a gene therapy for Parkinson’s disease, another for a salivary gland condition, and the Janssen program. Multiple programs for inherited retinal diseases are in Phase II trials, and there are candidates for additional indications at the IND stage.

Regulation of gene expression

“When we started the company,” Forbes recalls, “we saw a really big gap in the technology of gene therapy.” This gap was the inability to easily control gene expression after a gene was delivered to a patient. To fill it, the company “designed a platform technology based on RNA structure,” Forbes says. “[It] allowed us to completely and precisely control—with oral small molecules—the delivery of any peptide or protein in the body at any time.”

The platform technology, called Riboswitch, has enabled the delivery of multiple antibodies, peptides, and hormones, including epoetin, parathyroid hormone, growth hormone, glucan-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), and multiple gut peptides and combinations.

“Our ability to deliver any peptide, hormone, or antibody with a pill,” Forbes declares, “solves many, if not all, of the issues we’re seeing with the extensive use of the gut peptides for metabolism, such as efficacy, tolerability, muscle loss, and fat regain, as well as the manufacturing burden of producing large amounts of peptides outside the body.”

Manufacturing capabilities

Manufacturing is, in many ways, at the heart of the company. Recognizing the lack of broadly available and highly effective manufacturing processes for gene therapy, MeiraGTx built its own capacity in-house from the beginning. “We now have a proprietary process that can, within two to three months, take an AAV vector and fit it to a GMP process,” Forbes notes. This time frame, she predicts, will be reduced to a few weeks.

The company boasts two flexible and scalable viral vector facilities to provide appropriate product volumes throughout development, from Phase I trials through commercialization, using the same cells and same processes.

“Because we are the commercial manufacturer for Janssen, we also built our own quality control facility, so we can perform release and stability testing for our batches,” Forbes says. “We did that not because we wanted to, but because it wasn’t possible to get rapid, high-quality testing from the current CDMOs.”

This means the company can go from making IND quantities to commercial quantities without making large changes in the process. Additionally, she says that during dialogs with the FDA before MeiraGTx launched its first controlled study for xerostomia, “We were able to answer the questions about the assay within three weeks.”

“Having these internal capabilities,” Forbes points out, “saves two to three or maybe even four years in the development timeline of any one of our products.”

Future plans

MeiraGTx’s Riboswitch technology goes beyond gene therapy to newly emerging applications in which short-acting agonists act as drugs. “This is an ‘aha!’ moment we didn’t expect,” Forbes admits. “Most pharmaceuticals are inhibitors,” but there is an enormous world of activators—agonists such as GLP-1 and GIP, for example—that are short-acting. “Only a few of them have been turned into drugs.”

Forbes suggests that a better alternative to blasting the body constantly with a gene product would be the delivery of short-lived agonists, an approach that “appears to massively increase efficacy and tolerability.” For example, as Forbes says, switching on the chimeric antigen receptor (CAR) in a CAR T cell with a pill increases efficacy fourfold compared to the approved anti-CD-19 drug “and has important implications for safety and durability.”

Metabolism is an area of keen interest as the company moves forward. Forbes says it may be possible to inject a patient with the DNA template for GLP-1 or GIP, and then administer a daily pill to precisely control the timing and level of the peptide’s production. She adds that MeiraGTx has developed a peptide that is the target of myostatin inhibition and “actively enhances muscle.” (Muscle loss is a prominent downside to currently approved GLP-1 therapies.) The company is also working to address the regain of fat.

Forbes notes that MeiraGTx’s big goals are accompanied by big challenges—none greater, she stresses, than the need to “find a workforce that’s as good as the one we currently have.” 

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