Depending on the scientific expert, gene editing is just another sophisticated gene therapy tool in the fight against human diseases or a technological advance so remarkable it has the potential to change the course of human development and that of every other genus and species on the planet.

The American Society of Gene & Cell Therapy (ASGCT) timeline for gene editing begins 30 years ago with the first experiments in yeast cells. But only in the past five years with the emergence of CRISPR Cas9 systems – the most popular form of gene editing – has the technology been touted as a revolutionary advance in human drug development on the scale of commercialization of recombinant DNA technology in the late 1970s.

Many experts and investors have been quick to champion gene editing’s surgical-like potential for mending the root cause of everything from cancer to rare genetic diseases, such as sickle cell anemia, cystic fibrosis and muscular dystrophy. Others are more cautious, observing that significant technical challenges and considerations, such as pricing and public policy, remain to be solved before patients routinely use gene editing products.

Most, however, on either side would agree that gene editing technologies potentially represent a new era in drug development, enabling biopharmaceutical companies finally to unlock the secrets in the mountains of biological data generated by the success of the 1990s Human Genome Project. These revelations now can be put to work not only in fighting, but also curing, diseases.

As is the case with most biotechnology advances, innovative, emerging companies are leading the charge to create gene editing therapeutic products, and they have attracted significant investment from venture capitalists and pharmaceutical companies. How long this courtship lasts likely will depend on how quickly the innovators can overcome prickly problems, such as precision, delivery and off-target editing, and demonstrate some positive clinical results.   

WuXi AppTec – a leading global pharmaceutical and biopharmaceutical open access capability and technology platform – assists gene editing companies from discovery to manufacturing and beyond. An important element of this support involves offering a communications platform to facilitate the exchange of ideas among the most innovative companies and the creative people behind them.

 In this installment of WuXi’s new communications platform on the future of drug discovery and development, leading gene editing experts discuss the prospects for this exciting new technology.  They include Cellectis CEO André Choulika, Harvard University Genetics Professor George Church, MPM Capital Managing Director Mitchell Finer, Sangamo Therapeutics CEO Sandy Macrae, and Agenovir CEO Dirk Thye. Their complete interviews also are available on this website.

Gene editing is the newest genome engineering advance in the broader field of gene therapy, which has been a focus of clinical research for the more than three decades. Simply put, experts have likened gene editing to the find and replace or delete functions on a computer.

Using nucleases – enzymes that cleave specific DNA sequences in cells – gene editing technologies target specific disease-related genes to delete, repair or replace them. The technologies include homing endonucleases (or meganucleases), zinc finger nucleases (ZNFs), transcription activator-like effector nucleases (TALEN) and cluster regularly interspaced short palindromic repeats (CRISPR).

The CRISPR-Cas9 gene editing platform, which burst on the scene about five years ago, was named by Science magazine as the 2015 Breakthrough of the Year. It is the most popular of the gene editing technologies because of its simplicity and lower cost. It also is responsible for the stratospheric excitement surrounding the field among academic researchers, investors, entrepreneurs, biopharmaceutical executives and the public.

Although most of the initial attention in gene editing is directed at rare genetic human diseases, the technology has vast applications. It can be used to attack disease-causing viruses that invade humans as well as target prevention of their transmission by modifying the organisms, such as mosquitos, which spread them.

Gene editing may be able to end the shortage of human donor organs by growing them in pigs or in the laboratory. The technology is applicable in agriculture to improve plant and animal breeding techniques with benefits for farmers and consumers. In environmental protection, gene editing has the potential to strengthen organisms threatened by climate change and create new biofuels as a replacement for the fossil version.

Recently, scientists demonstrated gene editing could be used to correct disease-causing abnormalities in human embryos, a development certain to ratchet up the ethical debate over whether the technology should be restricted to somatic cells or extended to germline cells, altering people’s inherited genetic make-up.

Many of the technology’s advocates see no limits to its applicability in that it bestows on genetic researchers and drug developers the power of a red-pen wielding editor, tearing through not only whole pages of an author’s manuscript, but fine tuning specific words – all with a goal of changing, and hopefully improving, what now exists.

It took more than 30 years for the first gene therapy to reach the market. Predictions are rare on when a therapeutic gene editing product will achieve market approval. If the history of fits and starts in the clinical development of traditional gene therapy are any gauge, patience will soon replace some of the excitement.

Granted, therapeutic gene editing’s exponential development has benefitted from three decades of gene therapy-based research. CRISPR emerged as a possible clinical development candidate a handful of years ago, and the first clinical trial was approved in the U.S. in June 2016.

Still, MPM Capital Managing Director Mitchell H. Finer, says there are significant barriers to overcome, and he has some sobering observations for companies in the field.

“There has to be clinical benefit in an early stage clinical trial in five years otherwise the value (of these companies) is going to evaporate,” Finer predicts. “All the cancer vaccine companies in the 1990s had high valuations and then we saw them fail. The CRISPR companies have to generate meaningful clinical benefits.”

Where are we now?

Harvard University Genetics Professor George Church – one of the word’s pioneers in genomics and a developer of the CRISPR technology – says, “About 2,400 gene therapies have been approved for clinical trials” and “almost all of these involve adding a gene. A handful involves reducing gene function, such as RNAi (RNA interference), ZFNs and TALEN. Almost none involves precise gene editing.”

Church says most people are surprised when he tells them how many clinical trials are ongoing in the gene therapy field. That’s not the only surprise he holds. His candid assessment of the current applications of the technology he helped create, revealed further below, may raise more than a few eyebrows.

In surveying the gene editing field, MPM’s Finer observes, “The homing endonuclease space is still pretty wide open. Sangamo Therapeutics and Cellectis pretty much dominate the TALEN space between them” and Sangamo has ZFN technology. “The most interesting things,” he adds, “will be (CRISPR) Cas9 or related.”

The catch with CRISPR involves patent fights for control of the technology’s foundational intellectual property pitting the Universities of California and Vienna against Harvard University and Massachusetts Institute of Technology. As of this writing, the former group has prevailed in initial decisions in Europe and China with the latter faring better in the U.S.

When considering investments in CRISPR companies, Finer says, “I want somebody to tell me they are not dependent on previously existing intellectual property in CRISPR Cas9.”

Sangamo has been involved in gene and cell therapies since 1995. Its lead gene editing products use ZFNs to insert in vivo into patients’ cells a gene that produces proteins, which are deficient because of an abnormality in the inherited gene.

“We recently initiated three clinical trials of in vivo genome editing for people living with hemophilia B, MPS1 (Hurler syndrome) and MPS II (Hunter syndrome),” says Sangamo CEO Sandy Macrae. “Our ZFN-based product, delivered as a one-time intravenous dose, will permanently insert a functional gene encoding the missing protein into a specific site within the albumin gene of hepatocytes (liver cells).”

The goal is to cure these patients of their rare genetic diseases. “If we are successful,” Macrae observes, “we’ll open the door to the next frontier of medicine, where genome editing is a viable therapeutic approach to curing many other diseases.”

According to Sangamo, the company also has patents covering the TALEN technology. Macrae notes that around the same time Sangamo published its pre-clinical ZFN gene editing success, the company’s “scientists also published the first high-efficiency TAL nuclease architecture, which remains in use across the field.”

But he adds, “Due to clinical advantages in specificity and greater targeting flexibility Sangamo chose to focus its therapeutic programs on zinc finger proteins – specifically on ZFNs and zinc finger transcription factors for targeted gene regulation.”

Like Sangamo, Cellectis is not a newcomer to the gene therapy field. “We started in 1999 with homing endonucleases, named meganucleases, that were at the time the only existing gene editing technology,” says Cellectis CEO André Choulika.

The company then considered TALEN, which forms the bases of its lead cancer immunotherapy products. “Today, it is obvious that TALEN is by far the superior technology for therapeutic use,” Choulika contends.

He adds that Cellectis investigated using CRISPR Cas9 and discovered “it was very accessible to design. Even a high school kid could design a CRISPR. However, the precision and efficiency were far less than that with TALEN.”

Cellectis’ lead clinical development programs are focused on blood cancers, leukemia and multiple myeloma. Cellectis uses what it calls “off-the-shelf” allogeneic, gene edited CAR-T cells from healthy donors. In addition to editing the T-cells ex vivo to target the cancer, the donor cells are engineered to protect them from being recognized as foreign and destroyed by the patients’ immune systems.

Agenovir is one of the many companies that has emerged to take advantage of the CRISPR technology. It also reflects the technology’s broad application. The company is using the CRISPR Cas9 system to destroy disease-causing viruses inside human cells, such as human papilloma virus (HPV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV).

CEO Dirk Thye explains, “Agenovir has developed a variety of CRISPR-nuclease products that specifically target viral DNA. Our initial programs are aimed at viral disease targets for which delivery is less challenging. In the case of HPV, we use a topical application of our drug product within a lipid nanoparticle that attacks a local viral reservoir located within the epithelium at the surface of the body.”

Two other clinical development programs involve patients who receive bone marrow transplants and are susceptible to CMV and EBV infections. Here, Agenovir treats the hematopoietic cells ex vivo (before they are transplanted) with the CRISPR products so they can knock out the opportunistic viruses if they strike.

As for the patent issues related to CRISPR, Thye says, “The patent landscape for CRISPR Cas9 is particularly complicated right now. We believe that over the course of the next five years, the patent landscape will become clear and pathways for rational licensing will be established.”

At this stage in the development of gene editing, unleashing the technology’s enormous potential depends primarily on overcoming barriers to delivering the payload to cells, whether in vivo or ex vivo, and then once inside making sure the edits are on target.

“Some of these (gene editing) companies started out with lofty ideas of in vivo gene delivery and they miss the mark,” Finer says. “Ex vivo gene editing clearly is the easiest way to get genes into cells and there are lots of interesting targets.”

When it comes to CRISPR and other genome engineering technologies, he adds, “I think the questions we have are efficiency in vivo and off-target activity. I don’t think these technologies are show stoppers yet.”

As for turning ex vivo gene editing into a broadly marketable product, Finer says a key unanswered question is: “Are you going to have to identify a guide RNA patient by patient or can you come up with one size fits all in terms of guide RNA?”

Church, also a genetics professor at MIT, offers a panoramic view of gene editing technologies compared to the snapshots from entrepreneurs in the field. Today’s descriptions of gene editing are misleading, he says, as none of the existing product candidates represents what he defines as precise gene editing.

“To add a gene you can pretty much put it anywhere on the chromosome,” he explains. “To subtract or knock down a gene you can either put in an interfering molecule or you can bash the gene and make a mess, kind of a random mess.”

Precise gene editing, Church adds, would mean altering individual nucleoside components of DNA – adenine, cytosine, guanine and thymine. “For example, taking a thymine and changing it to adenine,” he says. “Or I want to move exactly four bases, not three, not five. That’s precise editing.”

For Church, it’s the difference between making a mess and elegantly changing the composition of a genetic abnormality. “Take sickle cell anemia,” he explains. “It’s a simple point mutation of one base from adenine to thymine. So you might just reverse that. But instead we’re going through all the hoops to figure out, well maybe there’s another gene that we could make a null in it and that would achieve the same result. Cystic fibrosis is another example, with exactly three bases deleted in the major form of the disease.”

Church suggests current product development efforts targeting genetic diseases are taking advantage of “low hanging fruit” because “the stuff way up there, it might be sour grapes.” But he adds, “If we could do precise genome editing as easily as we do knock out, we’d do it that way.”

Where are we headed?

So what does the future hold for translating the enormously promising science of gene editing into therapeutic products?

Even assuming companies score early clinical successes within Finer’s estimated five-year deadline for maintaining investor enthusiasm, they still face significant challenges in winning regulatory approval of these medicines and delivering them to patients’ bedsides for the broad applications predicted.

On the technical front, Sangamo’s Macrae acknowledges in vivo delivery of the gene editing products to cells remains problematic. “At the moment we all use AAVs (adeno-associated viral vectors) with strong tropism to certain organs, like the liver,” he says. “Resolving specific delivery mechanisms to other tissues will open other diseases to gene editing.”

For example, new vectors will be needed for delivery into the central nervous system to treat neurodegenerative diseases such as Alzheimer’s disease, and for delivery into lungs to treat cystic fibrosis. “The moment we can deliver zinc finger proteins beyond the liver,” he says, “the therapeutic potential of genome editing will open up dramatically.”

Cellectis’ Choulika agrees new vector technologies are needed and adds that off-target editing is another problem that must be solved. “The reduction of off-targets will be addressed by nucleases with a DNA protein interaction which will not involve a RNA guide,” he says.

Once the technical specifics of the products are resolved and regulatory success emerges, ramping up to commercial scale manufacturing becomes another daunting milestone, one that Thye, however, has no doubt will be achieved as the fledgling gene editing industry begins to mature.

“The relatively low number of vendors, less experience in GMP (Good Manufacturing Practices), limited experience in large-scale manufacturing and few clinical trial successes with manufactured drug product all represent challenges in this field,” Thye says. “However, there is a tremendous amount of time, money and effort allocated to the challenges by many companies in the gene editing field.”

Beyond market approval and manufacturing, another barrier looms – pricing, a public policy subject that involves more than scientists, entrepreneurs, and venture capitalists, which may require a whole new approach to health care reimbursement.

“The commercialization model will eventually need to be addressed and the medical community will find a solution once we cross that road,” Macrae says. “At that point, this also means that society will need to carefully consider how we view medicines that give you a cure for life as opposed to something you must take on a regular basis.”

For example, Glybera, the first gene therapy approved, was priced at $1.4 million for one treatment course, which is all that may be needed to cure its target, lipoprotein lipase deficiency. The price, the highest in history for a therapeutic, reportedly was based on the annual cost of treating patients with enzyme replacement therapies.

Although human drug development gets all the attention, Church again widens his lens to include other applications, such as those in agriculture and wild species, which already are in use. Here one concern involves creating gene drives to force inheritance of specific genetic traits, such as engineering mosquitos to prevent transmission of malaria.

“My group at Harvard was among the first to publicly note these issues and discuss solutions, including biocontainment, reversal drives and daisy drives,” Church says. The main issue, he observes, is that people want to be in control.

“They don’t want things escaping into the wild and not be able to bring it back in,” Church explains. “One of the problems we foresaw when we developed CRISPR gene drives was irreversibility. So we put some effort into reversibility and containment.”

Prickly problems aside, speculation on gene editing’s potential impact is as far-ranging as the technology’s applications.

Finer, the venture capitalist, says he looks at gene editing through the lens of a pharmaceutical developer. ”It is an important addition to the arsenal,” he says. “But if one is going to say gene editing is akin to splitting the atom, I would probably disagree.”

Church, the academician, is not so much smitten with gene editing technology as he is with the exponential progress it represents in developing a “new genome technology ecosystem,” which includes reading and writing genetic code.

“I think the real breakthrough here is a cluster of improvements on how you read and write DNA,” he says. “There’s this whole continuum – adding genes, subtracting genes and precise editing; and the fourth, the next thing, is being able to write whatever you want.”

Choulika, the entrepreneur, is more in tune with the professor than the banker. Gene editing, he says, represents “a major paradigm shift in the history of the Earth, far deeper than anything since the rise of Homo sapiens. Human fate is now within our hands.”