Addressing the American Society of Gene and Cell Therapy Annual Meeting in 2016, four years before being awarded a share of the Nobel Prize in Chemistry for pioneering research in CRISPR, Jennifer Doudna, PhD, began by sharing what has become an oft-repeated maxim in gene therapy by summing up the field’s biggest challenges:
“Delivery, delivery, delivery.”
Among those listening intently was Kunwoo Lee, PhD, a Korean postdoc in her University of California, Berkeley lab. That year, Lee joined two other collaborators with Doudna’s lab in launching a company focused on developing genetic medicines with tissue-selective in vivo delivery.
Lee recalled Doudna’s words this week as his company, GenEdit, signed a major multi-year collaboration and license agreement with Genentech, potentially worth up-to-$644 million, to discover and develop novel nanoparticles capable of delivering the Roche subsidiary’s nucleic acid-based treatments for autoimmune disease.
The collaboration, which was announced on Tuesday, aims to develop non-viral, non-lipid, hydrophilic nanoparticles (HNPs) discovered through GenEdit’s NanoGalaxy® platform. NanoGalaxy includes a library consisting of thousands of unique non-viral, non-lipid, hydrophilic polymer nanoparticles.
Using this combinatorial library of polymers, NanoGalaxy creates nanoparticles consisting of hydrophilic polymer backbones with diverse small-molecule side chains, all combined with a variety of structures to yield hundreds of thousands of structurally distinct polymers capable of targeting certain cells. The HNPs derived from these polymers can be further diversified by size and other properties, depending on where in the body they are needed to deliver their payloads.
GenEdit says its technology offers several advantages over other delivery methods, including tissue selectivity, payload flexibility, low immunogenicity, ability to re-dose, and ease of manufacturing. The size of functional payloads ranges from 20-basepair siRNA constructs to 10-kilobase constructs, well beyond the approximately 5 kb size limits associated with adeno-associated viruses (AAVs).
The polymer nanoparticles can encapsulate diverse payloads, according to GenEdit, including nucleic acids such as messenger RNA (mRNA), antisense oligonucleotides (ASOs), or silent RNA (siRNA); therapeutic proteins and CRISPRs.
“It really depends on the indication,” Lee said. Indications that require short-term gene expression are most suitable for mRNA, while siRNA is a better option for indications that require gene silencing and gene editors, for indications that need a more permanent effect.
“There are hundreds of gene editor types that we are seeing, either for cutting, replacing, or the insertion of the gene. But every single modality requires delivery,” Lee said.
Which delivery modality will GenEdit and Genentech pursue? The companies aren’t discussing specifics of their collaboration.
Targeted alternative to “sledgehammer”
“Until now, the way that we have approached autoimmune disorders is more like bringing a sledgehammer and breaking one pathway. We would just want to shut down the hyperactivated immune system by shutting down a certain pathway, but that also comes with some side effects for some patients, while others do not respond to that at all,” Lee said.
“Meantime we have now a much better understanding of what causes autoimmune disorders at either the antigen level or the pathway level. Then we can apply genetic medicine, and take a more specific or targeted approach,” Lee added. “We are very excited about using our technology in autoimmune applications, where it will open a new opportunity for patients.
Autoimmune and inflammatory diseases are within the “immunology” category, one of eight areas where Genentech is pursuing partnerships. (The other seven are cardiovascular and metabolic disease; oncology and cancer immunotherapy; infectious diseases, neuroscience, ophthalmology, research technologies (including “genomic medicines” and “targeted or intracellular delivery”), and digital and personalized healthcare.)
“Genentech and Roche really have a culture of bringing innovation to the clinic, and they are very, very interested in the autoimmune space. The fortunate part is that we are both in the same location, in South San Francisco,” Lee recalled. “While we were in conversation, we found that they were interested in a particular autoimmune application, and they were looking for the right technology. We got connected based on that.”
Roche agreed to pay GenEdit $15 million upfront and up to $629 million in payments tied to achieving near-term, preclinical, and clinical development, commercial, and net sales milestones—plus tiered royalties on global net sales of products developed through the partnership. Genentech will oversee preclinical, clinical, and regulatory development—as well as commercialization of products resulting from the use of GenEdit’s nanoparticles.
“We look for external innovation to complement our internal science to help advance transformative medicines for people living with autoimmune diseases,” James Sabry, global head of Roche Pharma Partnering, said in a statement.
Pursuing non-viral delivery
GenEdit is among genetic medicine developers seeking to develop non-viral delivery methods for delivering gene therapies and other genetic medicines, with the aim of avoiding the toxicities seen in clinical trials where patients have received high doses of AAV vectors—the subject of a 2021 FDA advisory committee hearing.
At the hearing, the briefing document prepared by FDA staffers referenced a commentary published in GEN in 2020 by Nicole Paulk, PhD, formerly of UC San Francisco and now the CEO, founder, and President of Siren Biotechnology, in which she stated: “In the long term, we need to shift our focus from ‘how can we safely use high doses?’ to ‘how can we design the vector so we don’t have to’.”
The FDA has approved five AAV-based gene therapies to date: Sarepta Therapeutics’ Elevidys® for some patients with Duchenne muscular dystrophy (DMD); CSL Behring/uniQure’s Hemgenix® for hemophilia B; Roche-owned Spark Therapeutics’ Luxturna® forRPE65 mutation-associated retinal dystrophy; BioMarin Pharmaceutical’s Roctavian® for adult severe hemophilia A; and Novartis’ Zolgensma® for spinal muscular atrophy.
Other companies pursuing non-viral gene therapy delivery that GEN reported last year include:
- Eyevensys uses DNA plasmids encoding therapeutic proteins to treat retinal diseases, such as wet age-related macular degeneration and geographic atrophy.
- Vesigen Therapeutics produces engineered versions of naturally occurring extracellular vesicles called ARMMs (ARRDC1-mediated microvesicles), as some non-viral options, such as lipid nanoparticles, can trigger the immune response as they carry a therapeutic cargo into the cytoplasm.
- CyGenica has engineered a negatively charged cell-penetrating protein that eschews endocytosis.
- And Avectas has developed an ex vivo cell editing technology called Solupore. Inside a closed single-use transfection chamber, cells are engineered by spraying them with a novel solution containing a gene editing cargo as well as an atomizer that creates a transient permeabilization to the cell membrane.
“UPS for gene editing”
Lee joined Niren Murthy, PhD, now a professor at UC Berkeley, and Hyo Min Park, PhD, to establish GenEdit in 2016, with the goal of establishing safe and effective strategies for delivering genetic treatments. At the time, they referred to their startup as “the UPS for gene editing.”
“We backed Kunwoo and Hyo Min for several reasons,” Bow Capital, a pre-seed investor in GenEdit, stated on its website. “We saw their passion for the space and their immense desire to create true societal good.” Lee is an academic “who very naturally crossed over to become an entrepreneur, which is rare, and something we value.”
Park brought years of valuable lab experience. “Together, they’ve built a sharp technical team with top researchers from all over the country,” Bow Capital observed.
A year later, GenEdit’s co-founders joined Doudna and 18 colleagues in publishing a paper in Nature Biomedical Engineering detailing an early triumph of their research, by reporting that they had engineered a gold nanoparticle technology for delivering CRISPR-Cas9 inside cells.
The researchers also showed in mice that a single injection of the delivery technology, called CRISPR-Gold, could repair the mutation that causes DMD. Mice treated with CRISPR-Gold showed an 18-times-higher correction rate and a two-fold increase in a strength and agility test compared to control groups.
CRISPR-Gold consists of 15-nanometer gold nanoparticles conjugated to thiol-modified oligonucleotides (DNA-Thiol), which were hybridized with single-stranded donor DNA and subsequently complexed with Cas9 and encapsulated by a polymer that disrupted the endosome of the cell. While the delivery technology showed success, with DNA damage similar to that of a typical DNA sequencing error in a typical cell that was not exposed to CRISPR (0.005 – 0.2%), GenEdit was concerned enough about the potential for DNA damage that it switched to gold-free delivery by engineering HNPs.
GenEdit raised an $8.5 million seed round in 2018, followed by completion of a $26-million Series A financing in 2021. GenEdit has raised a total $58.5 million in financing since it was established, including the $24 million in Series A1 financing that GenEdit also announced on Tuesday.
Proceeds from the series A1 are intended to support continued development of the NanoGalaxy platform and a pipeline of preclinical therapeutic candidates. GenEdit has not disclosed individual candidates within its pipeline, although Lee said the company is focusing on developing treatments for CNS disorders and extrahepatic disorders, in addition to the autoimmune therapies it is partnering with Genentech to develop.
The Genentech collaboration is GenEdit’s latest partnership with a biopharma partner. GenEdit launched an alliance with Sarepta in 2020 to develop gene editing therapies for neuromuscular diseases. The companies publicized their alliance and subsequent progress in 2022, with Sarepta paying GenEdit $57 million in near-term payments, plus “significant” payments tied to achieving development, regulatory, and commercial milestones, as well as tiered royalties on future product sales.
Lee declined to provide an update on the Sarepta collaboration.
GenEdit’s latest financing attracted new investors that included KDB Silicon Valley, Mirae Asset Venture Investment, ACVC Partners, Pathway Partners, LoftyRock Investment, Terra VC, K2 Investment, Dong-A ST, KIMCO and Huons—as well as existing investors Sequoia Capital, Korea Investment Partners, Woori Venture Partners, DAYLI Partners, KB Investment, IMM Investment, TIMEFOLIO Asset Management—and Eli Lilly.
Eli Lilly houses GenEdit among other startups at its Gateway Labs by Lilly, a shared innovation accelerator in South San Francisco. The site is one of two facilities for GenEdit, which also occupies a satellite lab in South Korea. Between the two facilities, GenEdit has a workforce of about 40 people.
“We have been gradually growing over time,” Lee said. “There will be some additional increase in FTEs that we expect for this collaboration we are starting, as well as for the ones that we are doing and currently talking to potential partners as well.”