Dyno Therapeutics CEO and co-founder Eric Kelsic, PhD

Dyno Therapeutics CEO and co-founder Eric Kelsic, PhD, likens his company’s development of transformative AI-designed adeno-associated virus (AAV) vectors for gene therapy to climbing a mountain—a hike, he says, that will be made easier by the company’s completion of a $100-million Series A financing.

The new financing, announced today, brings Dyno’s total financing raised to $109 million from investors, in addition to undisclosed upfront capital raised through collaborations with a combined potential value of $4 billion or more that Dyno has launched with three biopharma giants.

“We’re really excited by the Series A providing some extra energy to our climb up this really important mountain,” Kelsic told GEN Edge. “Our goal is to climb this mountain and get to the peak because the peak is where the best vector is found.”

“The top of that is great for everyone in terms of our ability to cure or treat and prevent disease,” Kelsic added.

While AAVs have emerged as the safest and most popular delivery vehicle for gene therapy over the past decade, a significant population—one study put it at more than half of humans—has been reported to have pre-existing immunity to naturally occurring forms of those delivery vectors, and thus cannot benefit from AAV gene therapies, according to research that includes studies published in 2013 and last year.

The size of the population with AAV vector immune response can range from 20-80%, depending on the natural serotype. Eleven AAV serotypes have been identified, with the best characterized and most commonly used being AAV2 (72%, according to a 2010 study in Human Gene Therapy, published by GEN publisher Mary Ann Liebert Inc.)

Dyno seeks to address that by commercializing CapsidMap, a delivery platform whose development started in 2015 in the lab of noted geneticist George M. Church, PhD, of Harvard Medical School, one of Dyno’s co-founders and the chair of its scientific advisory board.

“George had a key role in helping us to get here by helping us to identify what was the key problem. George ‘s lab is well known as a great place to go to develop technologies, which is why I went there,” said Kelsic, a former postdoc in the Church lab.

The scientific advisory board was expanded last month when Dyno appointed Debora Marks, PhD, of Harvard Medical School and the Broad Institute, and Nicole Paulk, PhD, of the University of California San Francisco. Paulk discussed the safety challenges of high-dose AAV gene therapies in a commentary published by GEN in July, and on a “GEN Live” episode the following month.

CapsidMap uses artificial intelligence to design novel capsids that confer improved functional properties to AAV vectors. At the core of CapsidMap, according to Dyno, are advanced search algorithms applying machine learning and the company’s large quantities of experimental data toward optimizing properties relevant for in vivo delivery.

These properties include increasing delivery efficiency and specificity to cell targets most relevant for genetic diseases, reducing the immunogenicity of the vector, increasing the packaging size, and improving manufacturability.

Reaching the top faster

“We are surveying the whole gene therapy landscape, sampling at all these different points. From that we then build this model of the whole terrain, and computationally we’re exploring all the different routes to the top. It’s kind-of like a pathfinding algorithm, and using that we can test billions of different ideas and prioritize those down to the millions that we can test experimentally,” Kelsic said. “With machine learning as a guide, that’s how we better ensure success at getting to the top, as well as enabling us to reach the top faster.”

By increasing specificity, Kelsic said, CapsidMap can make gene therapies more effective and safer by allowing for treatment with lower doses, thus reducing the cost of treatments and enhancing their safety.

The longstanding issue of dosage safety within gene therapy development resurfaced last month, when Adverum Biotechnologies acknowledged that a patient lost sight in the eye that was treated in a Phase II trial with the company’s lead gene therapy candidate ADVM-022 (AAV.7m8-aflibercept) for diabetic macular edema (DME).

Earlier this year, Kelsic, Church, and a third Dyno co-founder, Machine Learning Team Lead Sam Sinai, PhD, joined six colleagues from the company, Church’s lab, Harvard and its Wyss Institute for Biologically Inspired Engineering, Google Research, and University of Cambridge in detailing how they successfully used AI to design highly diverse capsid variants from an AAV virus, with the aim of identifying functional variants capable of evading the immune system.

In a study published last February in Nature Biotechnology, researchers reported how, focusing on a 28-amino-acid segment, they generated more than 200,000 variants of the AAV2 wildtype sequence. This yielded some 110,000 viable engineered capsids, half of which surpassed the average diversity of natural AAV serotype sequences with 12–29 mutations across the region.

“The key takeaway is, all of a sudden you can screen millions of variants without having to do a single experiment to figure out if it will package or not,” Sinai told GEN Edge in February. “One direction that we are working on in building models is a better ability to fine tune the product to make sure it succeeds in a particular group of patients and, eventually, a single patient.”

Sinai, Kelsic, Church, and colleagues had previously reported using an AI approach to engineering improved capsids in a study published in 2019 in Science. “Applied to AAV, such methods now enable the systematic optimization of natural capsids into synthetic variants with enhanced properties for emerging gene therapies.”

Among gene therapy developers applying CapsidMap are three biopharma giants that have inked partnerships with Dyno totaling potentially more than $4 billion:

  • In May 2020, Novartis and Sarepta Therapeutics launched a combined up-to-$2 billion in collaborations to develop gene therapies for eye and muscle diseases, respectively, based on Dyno’s platform.
  • Five months later in October, Roche and its Spark Therapeutics subsidiary agreed to explore CapsidMap-based gene therapies for central nervous system (CNS) and liver disorders—a collaboration that could potentially generate $1.8 billion-plus for Dyno.

“We want to achieve success there quickly, as well as expand those partnerships into new areas, and then we want to partner with others, both in those areas, as well as expand what’s possible with gene therapy into new organs,” Kelsic said.

Investors and biopharmas have shown growing interest in AAVs based on modified capsids by Dyno and other companies. In December, 4D Molecular Therapeutics went public through an initial public offering that raised $204.7 million in net proceeds. In February, Munich-based Sirion Biotech launched a collaboration of undisclosed value with Sanofi to develop new and modified AAV capsids for gene therapies targeting multiple unspecified “life-threatening disorders” affecting major human organs.

And in April, LogicBio Therapeutics granted CANbridge Pharmaceuticals a worldwide license for AAV sL65, the first capsid based on LogicBio’s sAAVy™ platform, to support development of CANbridge gene therapy programs for Fabry disease and Pompe disease, plus options for two additional indications. In return, CANbridge agreed to pay LogicBio $10 million upfront, up to $581 million in options payments plus clinical, regulatory, and commercial milestone payments; plus up to double-digit royalties on net sales.

Heart, kidney, and lung diseases

Dyno says it will use part of its proceeds from the financing to build on its current partnerships and launch new ones. The company plans to expand applications of its platform to heart, kidney, and lung diseases—where delivery challenges have limited the development of gene therapies.

Dyno also plans to grow its business development effort and other operations. Kelsic said the company plans to triple its workforce over the next two years, having doubled in size over the past 12 months to about 50 employees.

Kelsic said Dyno has no plans to expand into development of actual gene therapies, preferring to continue focusing instead on developing its capsid platform, with the aim of supplying novel AAVs to power all gene therapies.

“There’s huge potential for the field, which is currently limited by our ability to deliver to target organs and cell types We have focused on the platform and investing in that infrastructure, because we believe that’s going to be the fastest way to solve all these problems, because you can only do you know so much at once,” Kelsic said. “We’ve really been focused on that because we think that’s the way in which we can have a broader impact helping patients.”

Andreessen Horowitz led the $100 million Series A financing, with participation from new investors that include Casdin Capital, GV (formerly Google Ventures), Obvious Ventures and Lux Capital—as well as founding investors Polaris Partners, CRV, and KdT Venture.

Polaris and CRV co-led Dyno’s $9-million seed funding round in 2018, when the company spun out of Church’s lab.

As part of the Series A, Jorge Conde, General Partner at Andreessen Horowitz, is joining Dyno’s board of directors. Conde previously worked with another Church company, Knome.

“In addition to enabling transformative therapies, productive bio platforms can enable novel business models too,” Conde posted on Dyno’s blog, linking to a commentary written with Andreessen Horowitz partner Judy Savitskaya. “If AI is an ideal tool for designing a diverse array of novel AAVs with varied functions, AI-designed AAVs can accelerate and reshape the entire gene therapy industry.”

Kelsic said the Series A financing positions Dyno to both be “funded very well in the near term and have many options for bringing in additional financing in subsequent financing rounds.”

“I think [investors] were really drawn by the importance of the problem that we’re solving and how key that is to enabling gene therapy to reach its full potential—as well as the potential of the technology to solve that problem. Those two, in combination, are really what makes Dyno unique,” Kelsic said.

“We have been working to build these tools for years, and these tools took time to develop but, once we have them, then we can quickly go apply them to all the other climb all the other 50 mountains that no one’s even attempting today,” Kelsic added. “That’s what’s really going to enable the field of gene therapy to reach its full potential to treat more diseases and benefit a broader number of patients.”

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