Biotechnology research has brought patients therapies made by editing DNA. Roche aims be part of the next wave of genetic medicines with a focus on RNA. Its latest move in this strategy is a partnership with Ascidian Therapeutics, a startup with technology that edits RNA to address multiple mutations driving a disease.
According to terms of the alliance announced this past week, Roche is paying $42 million up front for rights to use Ascidian’s RNA exon-editing technology for certain neurological targets. Specific targets remain undisclosed, but Robert Bell, Ascidian’s senior vice president and head of research, says they are for diseases with severe unmet medical need.
“These are devastating diseases and patients are waiting for solutions, and others have tried solutions that have not worked,” he said. “Part of that is not fully understanding the nature of these diseases. RNA exon editing has a real potential to solve some of these issues that have not been able to be tackled.”
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Therapies made by editing genes employ an editing technology, such as CRISPR. The cutting is done by an enzyme that’s not native to the human body, which means it can spark an immune response. Meanwhile, the act of cutting DNA introduces the risk of off-target edits. Ascidian’s approach to genetic medicine is to focus on exons, which are protein-coding segments of RNA. Mutated exons can result in mutated proteins that cause disease.
Ascidian’s in vivo therapies are designed to excise disease-causing exons and replace them with functional ones. By editing the RNA before it is translated into protein, Ascidian aims to enable production of full-length, functional proteins. Bell says these proteins are expressed at the appropriate levels in the right cells and at the right time. This approach does not use exogenous enzymes, nor does it cut DNA, so it avoids immune responses or off-target edits that are risks with DNA-editing therapies.
Boston-based Ascidian was formed and incubated by venture capital firm Apple Tree Partners, which unveiled the startup in 2022. Since then, the company has advanced to the clinic with lead program ACDN-01, a potential treatment for Stargardt disease, an inherited vision-loss disorder that currently has no FDA-approved therapies. Bell said Ascidian selected Stargardt because it has a genetically defined target in the ABCA4 gene. The large size of the gene makes it difficult to treat with a gene therapy that replaces the mutated gene. The challenge with editing ABCA4 is that more than 1,000 mutations to this gene are associated with retinal disorders, making it impossible to develop a gene-editing therapy to address each one. By editing exons, Ascidian aims to address more of the mutations driving Stargardt. Preclinical data for ACDN-01 were presented in May during the annual meeting of the American Society of Gene & Cell Therapy. A Phase 1/2 clinical trial began earlier this year.
Chief Financial and Business Officer Dan Rosan said that as a company with a platform technology, partnering was always part of Ascidian’s long-term strategy. The startup’s progress with its lead internal program helped accelerate discussions with pharmaceutical companies. Roche is Ascidian’s first pharma partner.
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“They had a clear sense of the targets that they wanted to think about and we had a very collaborative, scientifically rigorous discussion about whether the technology would be applicable to those targets, and how,” Rosan said. “This was a situation in which there was a lot of scientific back and forth from the beginning.”
Roche has long had an interest in targeting RNA as a way of treating disease, particularly neurological disorders. The Swiss pharma giant’s relationship with Ionis Pharmaceuticals goes back more than a decade and yielded tominersen, an antisense oligonucleotide therapy that binds to messenger RNA to prevent production of the mutant protein that drives Huntington’s disease. Tominersen is in mid-stage clinical development. The two companies came together again last year, with Roche licensing rights to two of Ionis’s RNA-targeting therapeutic candidates for Alzheimer’s and Huntington’s.
Roche’s RNA aspirations have also led to collaborations with startups. The pharma giant is pursuing RNA interference therapies for neurodegenerative disorders under a partnership with Atalanta Therapeutics. It’s also working with Shape Therapeutics, a startup developing programmable RNA medicines to repair the genetic causes of disease. When the Shape alliance began in 2021, the focus was neuroscience and rare disease. Late last year, the collaboration expanded to include an undisclosed prevalent disease. Roche’s RNA-targeting strategy also encompasses small molecules, which the pharma giant is pursuing through collaborations with Arrakis Therapeutics, Ribometrix, and ReMix Therapeutics.
James Sabry, global head of pharma partnering at Roche, said in a prepared statement that the Ascidian alliance is an opportunity to harness RNA exon-editing technology that has the potential to edit multiple whole exons at the RNA level with a single treatment. The deal calls for Ascidian to handle discovery and certain preclinical work in collaboration with Roche. The pharma giant will handle other preclinical activities as well as clinical development, manufacturing, and if approved, commercialization. Ascidian could earn up to $1.8 billion in milestone payments.
Rosan said the upfront payment provides Ascidian with more capital to develop additional internal programs in neurology or other therapeutic areas. Though Ascidian’s lead program is for an inherited eye disease, the startup is not an ophthalmology company. Most of the genetically defined targets the company has been exploring are outside of the eye, Bell said. The Roche alliance is not exclusive. Ascidian may develop its own neurological therapies for targets not covered by the agreement. It may also pursue other targets with other companies.
“I think we’ll learn a lot (from Roche) about how we partner,” Rosan said. “We anticipate other partnerships, the right partner for the right target.”
Photo by Ascidian Therapeutics
