Egenesis Inc., a 2015 startup that has helped put xenotransplantation back on the table as a potentially viable option for organ transplant thanks to its founders' work using CRISPR gene editing technology, closed its first substantial financing, a $38 million series A expected to take development efforts through preclinical proof of concept.

It's a large raise given the early stage nature of Egenesis' work to date. Backers include Biomatics Capital and Arch Ventures Partners, which led the round, with participation from Khosla Ventures, Alta Partners, Alexandria Venture Investments, Heritage Provider Network, Berggruen Holdings North America Ltd., Uprising and Fan Ventures.

"The venture partners put a lot of trust and faith in the team and the technology," said Luhan Yang, co-founder and chief scientific officer.

The team boasts an impressive pedigree. Yang co-authored, along with famed geneticist – and Egenesis co-founder – George Church, one of the seminal papers published in Science in early 2013 detailing work using CRISPRs, or clustered regularly interspaced short palindromic repeats, to precisely edit mammalian cells. (See BioWorld Today, Jan. 4, 2013.)

Other members of the founding team include managing director Geoff Mackay, who previously helmed cell therapy firm Organogenesis Inc., and Harvard Medical School's Marc Güell, who invented the CRISPR-GA software for large-scale gene editing assessment.

"Right now we have a team of eight people at Cambridge, working to deliver human transplantable organs from genetically engineered pigs," Yang said.

The need is enormous. According to the FDA, 10 patients currently die every day in the U.S. while on the waiting list for organ transplant. In end-stage renal disease, for example, patient estimates are about 650,000 in the U.S.; yet, only about 100,000 are put on the list.

"But because of the limited supply, it's highly selective," Yang said. "Only about 20 to 30 percent" of people on the list end up receiving a transplant. "So human life is at stake."

And in Asia, where the culture does not encourage organ donation, the need is even greater. "In China, for example, there are 3 million people waiting but only a couple thousand donations per year," Yang said.

The Egenesis team is "really motivated . . . to create a world where there is no shortage of organs" for transplant, she told BioWorld Today.

Xenotransplantation – the process of transplanting organs or tissues across species, pigs to humans, for example – emerged as a potential method of dealing with the organ shortage. And work conducted during the 1990s generated interest but not success. "The technical hurdles were insurmountable," Yang said. "People were under the assumption that knocking out the antigen with an immunosuppressant" would be sufficient to prevent organ rejection, "but they underestimated how many modifications they would have to do, and there was no tool for doing them."

There was another problem. Given that pig organs are roughly the same at human organs in terms of size and physiology, they became the obvious alternative for human organ transplants. But pig DNA contains PERVs, or porcine endogenous retroviruses. "Once you co-culture the pig cell with the human cell, the virus will jump from pig genome to human genome," Yang explained.

In vitro evidence of that transmission prompted the FDA in 1997 to place a clinical hold on xenotransplantation, while subsequent efforts launched to find ways to monitor PERV transmission or block the viruses' ability to replicate. (See BioWorld Today, Jan. 23, 1998.)

But it was the advent of CRISPR that has proved a potential game-changer for xenotransplantation.

"The beauty of CRISPR is its ability to hit multiple parts in the genome at the same time," Yang said.

In an October 2015 issue of Science, Church, Yang and the team at the Wyss Institute for Biologically Inspired Engineering at Harvard Medical School, described using the CRISPR/Cas9 tool to make 62 simultaneous edits to the pig DNA, aimed at inactivating all the PERVs found in the pig genome.

"That broke the record of the number of modifications you can do in a mammalian system," Yang said. "We had a parallel program in the meantime, [in which] we were trying to do dozens of modifications to address the immunology issue." That work included modifying antigens known to trigger a human immune response.

Modifications to both PERVs and antigens are needed for eventual transplant into humans.

Getting to proof of concept

For Cambridge, Mass.-based Egenesis, human testing is still a ways down the road. With the recently closed series A, the firm will start with genomic engineering of pig cells and will clone a pig to use a bioreactor for organ maturation.

"We've entered the pig production phase now," Yang said, with the goal of "trying to produce pig 2.0 by the end of this year." After that comes preclinical proof-of-concept testing, in which it will test transplantation in a human immune system to evaluate compatibility and ensure there is no virus transmission.

The $38 million should carry the firm through "demonstration of proof of concept at the preclinical level," Yang said.

Concurrent with the financing, Egenesis added members to its board, including Boris Nikolic, whose firm, Biomatics Capital, announced the close of its initiatory fund Wednesday, bringing in $200 million, ahead of its $150 million target. Biomatics will dedicate the fund to genomics, digital health and data-driven health care technologies and anticipates investing in 15 to 20 companies with the latest fund, acting as series A lead investors in a majority of the deals. Biomatics said initial investments typically range from $5 million to $10 million, with up to $20 million over the life of the investment.

Other additions to Egenesis' board include Steven Gillis, of Arch Ventures, and Daniel Lynch, who is taking on the role of executive chairman. Lynch previously served as CEO of Imclone Systems Inc. and as executive chairman of Avila Therapeutics Inc. and Stromedix Inc.

Close of the financing fell roughly a month after the U.S. Patent and Trademark Office issued a decision of "no interference-in-fact" in CRISPR/Cas9 interference motion phase, a judgment that favored the Broad Institute at the Massachusetts Institute of Technology, which is aligned with Editas Medicine Inc., of Cambridge, Mass. – Church is listed as one of the founders of Editas over in the IP battle with the University of California at Berkeley. (See BioWorld Today, Feb. 16, 2017.)

Egenesis' news is only the latest in a string of CRISPR-based transactions. On Tuesday, Editas disclosed a research alliance with Allergan plc including its lead drug, LCA10, for Leber congenital amaurosis type 10, a genetic form of progressive blindness. Crispr Therapeutics AG, meanwhile, inked a deal through its Bayer-partnered joint venture, Casebia Therapeutics, gaining nonexclusive commercial-use rights to Maxcyte Inc.'s cell engineering platform to develop CRISPR/Cas9-based therapies for hemoglobin-related diseases and severe combined immunodeficiency. (See BioWorld Today, March 15, 2017.)