Exsilio Launches With $82M to Tackle Gene Therapy Challenges in Novel Approach

Pictured: An hourglass connected by strands of DNA

Pictured: An hourglass connected by strands of DNA

Exsilio Therapeutics emerged from stealth on Tuesday with a platform that leverages mRNA technology to develop redosable genomic medicines for a range of complex diseases.

Pictured: An hourglass connected by strands of DNA/Nicole Bean for BioSpace

2023 was a breakthrough year for the gene therapy space, including the first approved CRISPR-based therapy, with a record seven approvals and more expected in 2024. Despite these successes, stakeholders at last month’s American Society of Gene & Cell Therapy (ASGCT) annual meeting raised concerns about the regulatory challenges, manufacturing issues, clinical development timelines and outlook for commercialization.

However, a Boston-based biotech emerging from stealth on Tuesday—and armed with $82 million in Series A financing to develop its genomic medicines—contends it has the potential solutions to help address many of these challenges.

Tal Zaks, chair and interim CEO of Exsilio Therapeutics, told BioSpace that its genomic medicines are designed to insert new, whole genes into a cell through mRNA intermediates. Exsilio’s ability to use mRNA technology to deliver therapeutics via lipid nanoparticles means the biotech has an established mechanism to rely on, which also enables repeat dosing. Combined with the whole gene delivery into cells, this could allow for the treatment of diseases that are the function of multiple mutations along the gene, such as genetic illnesses, cancer or autoimmune disorders.

This approach to a potential new class of genomic medicines has drawn interest from prominent backers, with the Series A financing round being led by Novartis Venture Fund and Delos Capital, with participation from OrbiMed Insight Partners, J.P. Morgan Life Sciences Private Capital and CRISPR Therapeutics, among others. Exsilio will use the funds to leverage its platform, which combines predictive in-silico modeling and wet lab-based work, to identify a lead candidate. Zaks, the former chief medical officer of Moderna, said the aim is to create enough in vivo data to identify at least one clinical candidate.

When it comes to the biotech’s strategy for selecting this candidate, Zaks explained, “I learned with Moderna that when you’re starting something new, you always want to take the highest probability of success path. So, we will go into areas where the unmet need is clear and understood and where the lipid nanoparticle technology is already mature or maturing.”

Competitive Advantages

Zaks described the biotech’s technology as a bridge between the two current common approaches to gene therapy. On the one side, there is the approach that involves inserting a singular gene that relies on the use of viral vectors to deliver the DNA into the nucleus, such as Novartis’ Zolgensma; the other approach involves making precise changes in the DNA, such as by using CRISPR technology, but this is limited to small changes, he said.

Aaron Nelson, managing director at Novartis Venture Fund and an Exsilio board member, said in a statement that his fund was “captivated by Exsilio’s genomic medicines approach that stands to enable large-gene integration in a safe and redosable manner.”

The investment in Exsilio’s approach is based on its platform’s potential to deliver greater advantages that may address some of the common concerns over gene therapy. One commonly raised criticism is the price tag of gene therapies, where one-time treatments deliver savings on lifelong treatments but enter the market costing in the millions of dollars per dose. Using mRNA technology will allow a variety of cost-efficiencies, according to Zaks.

“The process can be done in pretty small containers or vats, and it takes a much shorter timeframe than typical biologics. That’s why mRNA is so cost-efficient,” Zaks said. “That has implications throughout the development life cycle, not just when you talk about being cost-effective for the patient at the end. But actually to discover and develop these medicines because it means that it’s cheaper to make and test early.”

Beyond ‘One-and-Done’

Another advantage is that the use of mRNA means it is not restricted to the ‘one-and-done’ approaches that currently exist, where viral vector-delivered gene therapies are limited in their dosing. This can be an issue if a patient’s immune system attacks or destroys the vector before it delivers the therapeutic package, which occurs in 30% to 70% of patients, according to ASGCT. As demonstrated by mRNA-based COVID-19 vaccines, repeated dosing can be achieved with this delivery method.

When it comes to genomic medicine, safety is a primary concern. Although the full details are not known, Pfizer last month revealed that a patient died in a clinical study of its investigational Duchenne muscular dystrophy gene therapy. Asked about his company’s approach to safety, Zaks said that Exsilio will focus on inserting its therapeutic genes into “safe harbor sites” of disease-relevant cells. He explained that these sites are areas within the genome that seem to tolerate gene insertions and small modifications, where other active genes and oncogenes do not exist.

Henry Chen, managing partner of Delos Capital and an Exsilio board member, said in a statement that “the vision of safely and durably integrating therapeutic genes into a patient’s genome requires using RNA-based payloads that can leverage clinically validated non-viral gene delivery technologies.”

Exsilio remains at the early stage of its journey in delivering potential therapeutics but with funding to advance its genomic medicines, at a time when biotech financing is only just beginning to recover, the Series A represents a strong endorsement of its technology.

Ben Hargreaves is a freelance science journalist based in Tosse, France. Reach him on LinkedIn.

Ben Hargreaves is a freelance science journalist based in Tosse, France. Reach him on LinkedIn.