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Brett Sansbury, Ph.D., is a research scientist and leader of the Discovery Research Group at the Gene Editing Institute, which has led the advancement of CRISPR science in Delaware. | PHOTO COURTESY OF CHRISTIANACARE[/caption]
Nature makes mistakes, even with our human genetic makeup. Not surprisingly, since discovery of the DNA double helix 70 years ago, scientists of various disciplines have been searching for ways to correct nature’s errors ever since.
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Dr. Eric Kmiec. executive director and chief scientific officer of the Gene Editing Institute at ChristianaCare, has been at the forefront of CRISPR research for decades. | PHOTO COURTESY OF CHRISTIANACARE[/caption]
Much of that search was theoretical until the 1990s when the Human Genome Project sequenced our genetic playbook. It was during this period that biochemist and molecular biologist Eric Kmiec began his research into gene therapy at Thomas Jefferson University in Philadelphia.
In a sense, Kmiec, whose work eventually brought him to Delaware in the early 2000s, was present at the creation of the field of gene therapy and has been active in its ups and frequent downs ever since. Today, he believes he and his research team are on the cusp of a major clinical breakthrough.
Now CEO of startup bioscience company CorriXR Therapeutics as well as executive director and chief scientific officer of the Gene Editing Institute at ChristianaCare, Kmiec is awaiting approval from the U.S. Food & Drug Administration (FDA) to begin human clinical trials of a cancer treatment therapy that would be among the first medical applications of what gene researchers have been seeking for almost three decades.
The work at CorriXR is one of two major genetic editing projects ongoing in Delaware. While Kmiec and his team, located at the University of Delaware’s STAR campus, are in consultation with the FDA, another research team at the Delaware Innovation Space at the DuPont Experimental Station campus is trying a specialized approach to gene editing that it hopes will have significant utility, first in plant crops and eventually in humans.
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Hijame Sakai | PHOTO COURTESY OF NAPIGEN[/caption]
In 2016, biochemist Hajime Sakai, a former scientist at DuPont as well as an ex-University of Delaware faculty member, co-founded Napigen to bring products to market by employing gene editing of mitochondrial DNA, organelles found in most cells where the biochemical processes of respiration and energy production occur.
These two teams have more in common than just gene editing. Both employ a scientific process called “CRISPR” that was pioneered in 2007 by food scientists working on yogurt culture, winning them the 2020 Nobel Prize in Chemistry. CRISPR/Cas9 has been described as a miraculous tool that allows scientists to perform microsurgery on DNA.
And the work being done especially by Kmiec, and more recently by Sakai, continues to place Delaware in the forefront of CRISPR research. CRISPR, or, more exactly, “clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9,” is a tool copied from a naturally occurring gene-editing system that bacteria use as an immune defense, including in the culture of yogurt.
Before CRISPR, gene editing was a somewhat suspect science within the larger field of gene therapy, Kmiec explained.
“Gene editing was treated as an anomaly at the time,” Kmiec said of his first days at Thomas Jefferson in the 1990s. “But other researchers wanted us to keep going just in case we were onto something. By contrast, researchers at the University of Pennsylvania thought that rare genetic diseases could be treated by cloning the gene and replacing the function of the defective gene.”
Then in 1999, a genetically engineered gene encased in a virus designed to combat a rare liver condition killed an 18-year-old patient at the University of Pennsylvania. Because the process had not been properly vetted and approved, the FDA stopped almost all research in gene therapy.
“It set the field back five to seven years,” Kmiec recalled. “Although it was not genetic editing, it terribly hurt the obtaining of grant money for research.”
That fatality and the discovery of CRISPR, Kmiec said, effectively switched research from gene replacement to gene editing. Even so, while Kmiec and others and discovered much about the mechanism of genes, “we had not been able to make a clinical difference.”
In 2015, Kmiec joined ChristianaCare because “someone convinced me that I needed to have my research embedded with cancer physicians who were working with the disease every day.” In recent years, one of Kmiec’s researchers at the center, Brett Sansbury, learned how to replace a defective gene in a sequence, but, while that part of the process worked, it changed the following gene as well – success and setback at the same time.
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Gene editing technology has the potential to not only treat diseases but also make existing treatments more effective. | PHOTO COURTESY OF CHRISTIANACARE[/caption]
Meanwhile, Kmiec has been working on a different way to use CRISPR, not as a primary therapy itself but as a potential adjunct treatment to enhance existing methods of cancer treatment. Although there are still no approved gene-editing therapies, cancer and two other diseases, sickle cell and beta thalassemia, both diseases caused by single-gene, single-nucleotide mutations, have become the primary targets within the gene-editing field.
To that end, for the past seven years members of the ChristianaCare gene-editing team have been working with a product that “in shorthand is called ‘R34G,’” Kmiec said, that is geared to knock out a gene the prevents other existing cancer therapies from working as well as they might.
R34G, which Kmiec said has strong patent protection, also expands the vocabulary of gene therapy, following on “gene replacement,” “gene cloning” and “gene editing.”
“When I write papers and proposals, I kept trying to find new ways to describe the process,” Kmiec said, “including ‘gene knockout’ and ‘gene displacement.’”
According to Kmiec, most cancer patients seldom complete more than 10% of their course of chemotherapy treatment, primarily because they can’t tolerate the side effects or they die from the disease.
“We believe we can raise this to 70% to 80%, which would be transformative,” he said.
For trial purposes, the CorriXR team decided to work with only one solid cancer target – lung cancer, which is also one of the deadliest – instead of broader applications. If it is effective in that cancer, they reasoned, then there will be a whole range of targeted treatments that could follow.
For several reasons, including fundraising, ChristianCare decided to spin off this part of the business as a separate company and physically move it from the Helen F. Graham Cancer Center on the main hospital campus to the UD’s STAR Campus, although Kmiec still maintains his position with the gene institute.
“The Gene Institute wants to continue to be an engine of innovation” for other medical advances, he said, “and it is financially important for ChristianaCare, like other health care systems, to establish these streams of revenue.”
For example, researcher Sansbury also invented a valuable teaching tool, “CRISPR in a Box,” in association with the Delaware Technical Community College that is now being marketing by Carolina Biological Supply. The Institute also has an important role in education and maintains a Learning Lab available to all students as a source of classes about CRISPR and related technologies.
Of course, the FDA has a clock and calendar of its own for reviewing and approving – or not approving – drug therapies from one stage to another based on their safety and efficacy evaluations as well as where it fits into the agency’s overall approvals agenda. Nevertheless, Kmiec is hoping that later this year or sometime next, the first lung cancer patients will be treated in clinical trials using R34G along with standard therapy.
While Kmiec and his team were midway in their development of R34G, in early 2019 Hajime Sakai was setting up shop in the empty offices as CEO of his newly created company, Napigen, in the Innovation Space. Like Kmiec, Sakai had been working in genetic therapy for almost two decades, but in his case it was with DuPont’s then Pioneer division. His work was interrupted in 2016 when he left the company in a downsizing move.
That year, as Sakai sat in the empty offices, he looked out his window and said, “I can see the building where I used to work, and some of the equipment we now have here in Innovation Space is from our old labs.” This was the year before the COVID pandemic struck, disrupting everyone’s plans, including those of Napigen.
Napigen, Sakai explained at the time, was the brainchild of four men, the other three from San Francisco.
“The other three had full-time jobs,” Sakai said with a laugh. “While I was getting over the shock of not having one. We knew that CRISPR was not being used for editing mitochondria DNA, and we came up with an idea on how to do it.”
As with Kmiec in humans, Sakai had a specific set of targets in crop plants – to develop hybrid seed technology in wheat and rice through gene editing of plant mitochondria to enhance crop production.
Today, with nine employees and a 2022 round of funding that netted $7.85 million in operational revenue, Napigen is still working on launching its first approved products.
Kmiec also knows that getting funding can be almost as difficult as achieving results in the lab and in trials.
“Although Delaware is a great place to do research, it doesn’t yet have the track record of places like Philadelphia for attracting investment capital,” he said.
And, now heading a spinoff company, Kmiec has twin roles at CorriXR – bringing new health care products to market as well as taking to the road to find funding to support that research.
“I’ll be going to the BIO International meeting in Boston the first week of June, and we have a spot in Start-Up Stadium [a major Shark Tank-style competition attended by large investment companies],” Kmiec said in late May. “I’m getting pretty used to explaining CRISPR and everything we do in five minutes.
“But when you’ve been working in gene therapy for 30 years and with CRISPR for 15, even five minutes may be critical to achieving success.”
