Delivery & Safety Top Concerns as BIO-Europe Plumbs Future of Gene Therapy

Cell and Gene Therapy

Cell and gene therapies are at an inflection point, as increasing quantities of clinical data highlight both their potential and their challenges before they can become mainstream therapies treating genetic diseases. Chief among them, according to panelists at The Future of Gene Therapies session at BIO-Europe 2021 – Digital, October 25-28, are safety and delivery.

A lot of pioneering developers are pushing the boundaries of science to overcome those issues, Sarah Jims, panel moderator and principal at Triangle Insights Group, pointed out.

Haya Therapeutics, for instance, is trying to reprogram the regulatory genome. The company is focused on fibrosis.  “We are leveraging well-established modalities. In targeting long non-coding RNAs (lncRNAs) – a new class of molecules that is very important in regulating how the genome responds to the environment – we leverage antisense oligonucleotides,” Samir Ounzain, CEO and scientific co-founder, told the virtual audience.

When Jims asked what keeps him up nights, he said, “targeting – how we can target our molecules in the relevant tissues of interest (the heart and lung). 

“We’re going after a first-in-biology therapeutic target,” Ounzain elaborated. “So, while we’re using quite well-validated modalities, we need to understand how these modalities interact with our target molecules and…understand their risks.”

For Novo Nordisk, the answer was “safety.” Novo Nordisk has worked in cell therapy for a while, but as Tomas Landh, innovation sourcing VP and senior principal scientist, said, “We’re fairly new to gene therapy.”

From an investor’s perspective, Regina Hodits, general partner at Wellington Partners, cited the cost of therapy as a priority. She said she is concerned about companies’ strategies regarding therapies’ cost-benefit ratios and how they can be managed to enable such therapies to become commonplace. “Related to that,” she said, “is manufacturing, cost of goods, standardization, dosing and dosing regimens.” The goal is to bring the cost of cell and gene therapy in line with the costs of other therapies so they can be reimbursed more readily.

Of these many issues, the panelists focused most upon delivery. After years spent developing viral vectors as delivery vehicles, “we’re seeing new particles and new vectors developed. There’s a really vibrant environment to address this,” Landh said. The development of hybrid particles, including lipid nanoparticle coatings for viral vectors, appears to address delivery as well as immunogenicity, he added.

Aside from local administration, “There are two approaches to decreasing toxicity,” Landh continued. “One is to de-target the liver. Another is to increase use of tropismal viral vectors, which have a preference for certain tissues and cells.” Research so far has been dominated by work involving tropism for skeletal muscle and cardiomyocytes, but there are efforts in other tissues as well.

Delving deeper, Ounzain added, “It’s becoming apparent that we can look at the individual cell types, their differences, and the states associated with them in the disease process.” In Haya Therapeutics’ quest to determine exactly where the specificity and selectivity of responses is hard-wired, it is focusing on the non-coding portion of the gene. “This is where we believe we can find the highly selective, highly specific targets.

“There’s a lot of work to do…in terms of how to get modalities against those targets to hit them at the right time and place,” Ounzain continued. “We’re doing a lot internally in the nucleic acid field to find ways to conjugate the nucleic acids to improve extrahepatic delivery.”

Researchers are also trying to determine which parts of the viral vectors used are causing immunogenicity. Therefore, Landh called for a deep dive into the intracellular trafficking of viral vectors. Current solutions to the immunogenicity problem are hardly new. They involve coating proteins with lipids and creating lipid nanoparticles.

One newer possibility is to create antibody conjugates. But, Landh cautioned, “We still lack the clinical proof that these will translate. Very few targets are static. It comes back to balancing risks and benefits.”

Another option, he said, is “to increase translocation and transport of the receptor (possibly by using small molecule switches) so it is visible when you give the dose.” The downside is that this requires pretreatment, “so this is not optimal.” 

A better understanding of biology may change this discussion dramatically. In the next few years, Ounzain said he expects to see “interesting advances in where disease-causing regulatory processes are happening, in terms of compartments within the nucleus and cytoplasm.” This could lead to the ability to target these disease-specific compartments.

While the mechanics of cell and gene therapy are garnering attention today, their introduction also will require improvements to clinical strategy, Hodits cautioned. “Adjuvant therapies will be very important,” she said, particularly at the point beyond which the immune system can no longer help. Therefore, “therapies must line up to reality. “All our new therapies, whether in oncology or fibrosis, will be done against the background of what’s already there,” and the overall effects must be considered.

“Checkpoint inhibitors, for example, will be a part of the patient journey, yet we have seen strong side effects when cell therapy was administered atop checkpoint therapy. People have ended up in the intensive care unit,” Hodits said. “Look at this from a humane point of view. Therapy is about quality of life, not just length of life.”

Cell and gene therapy is at a very exciting time right now. As Ounzain pointed out, “nature has left a lot of clues in the genome and we are only now scratching the surface.”

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