Are we closer than we think to personalized genetic medicine?
When gene editing exploded onto the scene over three decades ago, it brought previously inconceivable disease treatment and potentially curative therapies into view. Today, gene editing remains one of the most gripping topics in biopharma — and a recent wave of partnerships may move the industry even closer to broad, curative treatment for genetic disease.
Discoveries across the natural environment deriving in vivo and ex vivo biotechnologies have ushered a floodgate of development possibilities. With giants like Bayer, Moderna, Vertex and others signaling that gene editing will be a key driver of their future pipelines, how will the industry leverage this new frontier of genomic technology?
A panel sponsored by Metagenomi and moderated by Endpoints News at the 2022 BIO International Convention convened an integrated group of thought leaders, leading scientists and investors to discuss the best practices to develop safe, efficacious gene therapies for the future. Here we capture insights from each perspective and panelist.
Expanding the gene editing toolbox through metagenomics
Most genetic modification trials today employ the revolutionary CRISPR-Cas9 method of DNA cutting, whose creators were awarded the Nobel Prize in chemistry just two years ago. While CRISPR-Cas9 techniques may provide a chance to treat some gene-related diseases, more innovation is needed to unlock the full potential of gene editing. With that goal in mind, Metagenomi is leading a new wave of startups looking to create powerful next-generation gene editing systems that can enable and accelerate the discovery and development of customized gene editing therapies across a wider range of genetic diseases and tissues.
Backed by $300 million, Metagenomi is combing the world’s natural microbial environment to discover breakthrough gene editing systems capable of editing DNA more precisely than current technology can. The science behind the company is metagenomics, which examines the genealogical composition of microbes from rich, natural environments such as hot springs, wetlands and salt flats. It’s a science that was pioneered by Metagenomi’s CEO and founder, Brian C. Thomas, who spent two decades dedicated to scientific research at UC Berkeley.
“Using metagenomics, we’re tapping into four billion years of microbial evolution, and the answers are there,” said Thomas. “We haven’t had to spend significant amounts of time in the lab engineering these enzymes in order to attain the high levels of activity that they’re able to hit, because they’ve been optimized naturally.”
The company is rapidly building the world’s largest, most diverse toolbox of both CRISPR and non-CRISPR-based gene editing systems through its proprietary discovery and analysis engine. This approach recovers DNA from natural samples and uses advanced AI-based cloud computing to reveal novel cellular machinery from previously unstudied organisms that can be optimized for therapeutic applications. Having a wider selection of modular tools enables scientists and healthcare providers to target aggressive cancers, rare diseases and other complexities as they seek to make a difference for patients.
Solving genetic editing challenges
So far Metagenomi has identified thousands of novel enzymes, many of which are ultra-small and display unique characteristics for enhanced gene editing applications. Compared to current editing systems, which are based on a few, large enzymes with targeting and delivery issues, Metagenomi systems offer flexibility. This broad enzyme diversity and smaller size enables greater efficiency, specificity and genome targetability, resulting in enhanced patient safety.
“[As] we started our survey in the natural environment of these unique nucleases, we tried to find characteristics that would really be beneficial with current delivery capabilities,” said Thomas. He noted that the company is still exploring the biochemical properties of its unique nucleases, including greater stability and resilience due to their origins in extreme environments, where pH and temperature, for example, are wildly atypical.
The company’s toolbox is currently weighted toward CRISPR-based systems but is expanding to include targeted integration of large DNA fragments, base editing and other types of gene editing tools.
Propelling in vivo and ex vivo therapies through partnerships
Metagenomi’s pipeline focuses on deploying its wholly-owned diverse toolbox in both in vivo and ex vivo applications. “As we started to develop these tools from the natural environment, we realized they had characteristics and properties that could make them unique in either of those settings,” noted Thomas. “From a business point of view, we’ve really focused on a partnership strategy around leveraging both of these technology applications.” In addition to enabling partners, Metagenomi also has a wholly-owned pipeline of next-generation therapies developed using the company’s novel technologies.
Moderna realized a partnership with Metagenomi — which was announced last year — could help differentiate it as an in vivo market leader in the future, including through genetic system reprogramming. The research collaboration will combine Metagenomi’s gene editing systems with Moderna’s mRNA technologies to develop innovative in vivo gene editing therapeutics targeting various genetic diseases.
“When working with partners like Metagenomi, we can actually create the next generation of functional genomic factors that combine mRNA technology and the powers of chain manufacturing,” explained Eric Huang, Moderna Genomics’ chief scientific officer. “That’s our blue-sky ambition and goal … combining that knowhow, the future technology generation, as well as Moderna’s manufacturing prowess, to really make personalized genetic medicine into reality” in years to come.
The Metagenomi team is also “excited about the fact that in the ex vivo cell therapy space, where the gene editing component is a tool to create a more impactful and powerful cell product, there’s a lot of room for development,” shared Thomas.
In fact, the company just announced a partnership with startup Affini-T Therapeutics to advance next-generation ex vivo T-cell receptor therapies — or TCR — for patients with solid tumors. The work will target core oncogenic drivers using Metagenomi’s proprietary gene editing systems to promote sustained clinical outcomes for cancer patients. “Solid tumors are really the next frontier in oncology,” noted Aude Chapuis, co-founder of Affini-T, associate professor at the Fred Hutchinson Cancer Center and a scientific advisor to Metagenomi. “We’re interested in TCR technology because it is able to target intracellular antigens … [so] we can really broaden the number of proteins that we’re targeting,” she said. “Ultimately, the non-viral gene editing is going to be extremely valuable for the TCR field in particular.”
Affini-T aims to perform multiple genetic edits of varying combinations across proteins, an endeavor fraught with challenges, Chapuis explained. But Metagenomi’s toolbox offers promise for editing efficiency and targeting: “I think Metagenomi has so many enzymes, so many possibilities, so that will help us choose the right ones to be able to achieve the goals,” she said. Thomas concurred, adding that Metagenomi is, “very pleased to see that our most characterized systems are attaining very high levels of efficiency across multiple loci at once.”
Jürgen Eckhardt, head of Leaps by Bayer, the pharmaceutical giant’s early-stage investment arm, counts Metagenomi and Affini-T within its portfolio. Both companies satisfied the investor’s key questions: “Is this a big unmet medical need? Is this something where we see huge potential to make a step change? Is this something where we see huge potential to go from therapy to cure?” he said. Eckhardt believes we are in the very early days of gene editing.“There are thousands, hundreds of thousands, millions more, potentially [enzyme nucleases to be discovered]…. That’s what led us to make an investment in Metagenomi.”
Other investors are similarly interested in tapping into the company’s discovery engine to probe its possibilities. Metagenomi’s discovery platform was a driving factor in the investor commitment for their oversubscribed Series B, which closed with $175 million in funding earlier this year.
Mitigating risk: a critical priority
With an eye toward the clinic, panelists noted the importance of continued vigilance in monitoring and mitigating the risk associated with gene editing. Draft FDA guidance released in March calls for careful monitoring of genome editing risks, such as unintended consequences and unknown long-term effects of on- and off-target editing. The agency recommends at least 15 years of long-term follow-up after clinical trials of gene editing treatments.
Gene therapy companies want to avoid the fate of Allogene, which was temporarily forced to suspend clinical operations until investigators concluded there was no connection between the company’s therapy and chromosomal changes detected in a patient. Strong communication with regulatory agencies and careful attention to preclinical data are critical, especially since preclinical false positives and false negatives can muddy the translation to the clinical setting, noted Will Dere, a Metagenomi board member, professor of internal medicine and associate vice president of research at the University of Utah Health Sciences Center.
Given the infancy of the field, Thomas emphasized, scientists are just beginning to understand off-target activities and how they culminate in problematic outcomes. Recently announced ex vivo therapies may involve as many as a dozen different edits within a single product — but an enzyme that is highly targeted and opens a genome at a single location at a time could mitigate the risk of chromosomal rearrangement. New technologies, like Metagenomi’s base editors, eliminate the need to create a double-strand break.
Huang noted that while Moderna is looking for alternatives to double-strand break to avoid risk where possible, chromosomal rearrangement is not frequently reported. Chapuis pointed to the field’s delicate balancing act in working to reduce risk while recognizing that the patients receiving modified cells are typically end-stage patients in phase one trials.
Looking toward a future of possibilities
The energy around gene editing is here to stay, panelists agreed. “One of the big reasons why there is so much excitement about gene editing is that this is the path to curative therapies…. That’s where the industry really wants to go,” noted moderator John Carroll of Endpoints News. “They want to come up with curative therapies … rather than just control symptoms or keep people on a steady plane.”
Noting the existence of thousands of different cancers and the reality that fewer than 10 percent of rare disease have therapies – with cures rarer still — Dere acknowledged that “when you look at our ability to cure patients or to provide longstanding remissions, we have a ways to go still, a long ways to go.” But assessing the field after decades in academic and industry, he sees a world of hope. “The breadth of possibilities with gene editing, with the approach and the platforms that Metagenomi provides, are really quite significant …. The possibilities here for more targeted, more specific and more efficient gene editing are tremendous,” he emphasized. “With the pandemic, the emergence and critical importance of the platform of messenger RNA in terms of therapeutics is incredible.”
Harnessing the potential of metagenomics is what motivates Thomas’ team to drive forward. “When you start to wade through this incredible data from these organisms that we’ve never seen before, we’ve never studied in a lab or cultivated, it becomes really exciting that there are possibilities there that we’re just now beginning to understand,” he said.