Gene therapy faced many challenges in its early days, but scientific advances, drug approvals and millions in investment have accelerated research in the gene therapy field. WuXi AppTec Communications has begun a new series profiling some of the companies developing novel and unique approaches to making gene therapy even more effective in treating intractable diseases. One such company is OncoSenX, based in Seattle.

OncoSenX believes “The next generation in cancer therapies will be more targeted with fewer side effects….and should be fought with genetic information.” The company is using brand new technology to develop transient gene therapies for solid tumors in cancers such as lung and prostate. They work by delivering genetic programs (DNA) that cause cancerous cells to commit suicide via apoptosis and/or express immunotherapeutic proteins that “flag” them for the immune system to aid in their removal.

WuXi discussed OncoSenX’s new gene therapy technology, and what this technology could offer in the future, with company CEO, Chairman and co-founder Matthew Scholz. A serial entrepreneur with a background in computer security and immunology, Matt is also the founder and CEO of Oisín Biotechnologies and former CEO of Immusoft, a biotech firm developing a breakthrough technology that will turn a patient’s B cells into miniature drug factories. He’s a graduate of the University of Washington and a frequent speaker at the UW School of Business.

WuXi: The promise of gene therapy has been around for decades. How has gene therapy research progressed over the past 20 years? Do you anticipate a wave of new approvals coming over the next 5 to 10 years?

Matthew Scholz: People have wanted to manipulate DNA ever since they knew what DNA was, of course – but as with any new technology, it took a long time for the field to develop. The last 20 years in particular have borne witness to extraordinary progress. They weren’t without challenging circumstances, of course: the 2000s began with the field reeling from the death of Jesse Gelsinger, a sobering event that would chill research and funding for some time, but most recently, we’ve seen the approval of several gene therapies, billions of dollars of investment and renewed excitement about what is possible. There are currently hundreds of gene therapies in clinical trials and I fully expect a commensurate wave of approvals in the future.

WuXi: What kinds of diseases are targeted with gene therapies?

Matthew Scholz: The first wave of treatments mostly targeted rare monogenic diseases, but now the field is largely dominated by oncology therapeutics. There aren’t many limits on what diseases could be treated with gene therapies, but given their expense and risk, today they are primarily focused on life-threatening or severely debilitating diseases.

The gene therapies we’re developing have compelling advantages in these respects. They should be far less expensive to produce at scale. This is largely due to the fact that we don’t need to grow viruses and that it’s an off-the-shelf product with no ex vivo cell culture. Our therapies should be far less toxic than chemotherapies and more broadly applicable & scalable than CAR-T cell therapies. In many respects what we’re building can really be thought of as the next generation of I-O therapeutics.

WuXi: What scientific advances are needed to make gene therapies more effective? Is delivery still one of the major challenges?

Matthew Scholz: Despite therapeutic developers’ best efforts, delivery remains the Achilles heel of gene therapy. It is less of a challenge for ex vivo gene-modified cell therapies, but there are many tissues one cannot take out of the body to modify. Viruses – adeno-associated viruses specifically – are the primary way of delivering DNA in vivo, and they are fraught with problems. They are exceedingly expensive to manufacture at scales needed for systemic delivery in adults. They have a very limited DNA cargo capacity and they’re also immunogenic, so repeat dosing isn’t feasible. The emergence of a delivery vector that addresses these limitations would be a transformative development for the field.

WuXi: Will gene therapies ever be commonplace? If so, how soon?

Matthew Scholz: Maybe not commonplace in the near future, but certainly more common. I think we’ll continue to see people preferring pills containing small molecule drugs that can be taken easily and mass produced cheaply. With that said, I think we are approaching the limit of what small molecule drugs can do. The more we learn about human biology, the more personalized and targeted our treatments become.

At the root of biology is the code of life – DNA – so one way or another, I think we’ll end up increasingly building treatments that manipulate genes and their expression. If we look further into the future, say 20-50 years, I think it’s possible that gene therapies will start to be used prophylactically and therefore become quite commonplace.

WuXi: What are the risks and limitations of gene therapies?

Matthew Scholz: The primary risk of gene therapies in general is an unintended integration event that leads to uncontrolled cell proliferation (cancer), though every treatment will have its own set of attendant risks. Some of the more significant limitations of today’s technologies are: the small payload capacity of the delivery vectors, inefficient transduction of the target cells (especially in vivo), immunogenicity of the delivery vectors and manufacturing constraints.

WuXi: What gene therapies are you developing and how do they work?

Matthew Scholz: We’re developing transient gene therapies for solid tumors – cancers such as lung and prostate. They work by delivering genetic programs (DNA) that cause cancerous cells to commit suicide via apoptosis and/or express immunotherapeutic proteins that “flag” them for the immune system to aid in their removal. Our first therapeutics will directly kill cancerous cells with a suicide gene, whereas our second-generation treatments will also actively engage the patient’s immune system. This is a radically different approach than traditional cancer therapeutics or even other gene therapies for cancer.

The data we’ve generated so far is really astounding! We can reduce the size of solid tumors in rodents by 90 percent with a single systemic IV injection without any detectable off-target toxicity. It’s also well-tolerated in non-human primates even at massive doses and, unlike viruses, our therapeutic can be administered repeatedly.

WuXi:  How does your approach differ from other gene therapy companies?

Matthew Scholz: We are killing cells based on their genetics, specifically their transcriptional activity. We deliver the DNA in vivo systemically with a unique lipid nanoparticle (LNP). The LNP is neutrally charged so it doesn’t have the toxicity associated with other LNPs on the market today. It gains entry into cells with a fusogenic peptide on its surface that mixes the lipids of the LNP with the lipids in a cell’s membrane. This results in the DNA being deposited directly in the cytoplasm, bypassing the endocytotic pathway entirely. Since the peptide fuses with cellular membranes, its delivery is indiscriminate – it dumps the DNA payload into any cell in comes in contact with. The DNA payload itself determines which cells are killed.

For example, our first therapeutic targets cells have elevated levels of p53 transcription factors. P53 is a tumor suppressor; a cell will typically activate p53 when it detects something, like DNA damage, that needs to be addressed before the cell should be allowed to divide. Since p53 prevents cells from dividing and cancerous cells divide uncontrollably, many cancers have mutated or otherwise broken the p53 gene in the process of becoming cancer. What’s important about this from our perspective is that when p53 is mutated or ablated, the cell often tries to rescue it by making more p53 transcription factors – this is analogous to a person smashing a button harder or repeatedly when it doesn’t work. Our DNA payload encodes a suicide gene that is controlled by a synthetic p53 promoter. That means that damaged cells with elevated levels of p53 transcription factors will read our DNA payload (the suicide gene) and die, whereas healthy cells with normal levels of p53 transcription factors will not read the DNA payload and remain unharmed.

We’ve effectively taken targeting out of the realm of chemistry and into the realm of information. This approach allows us to even go a step further and implement Boolean logic in DNA. We can build logic gates in DNA (such as IF /AND/NOT) and make the targeting very specific based on the transcriptional activity of the cells – it’s a radically different approach than others are taking.

Our LNP is also far less expensive to produce than viral vectors: the most expensive part is the DNA itself. It can also be made very rapidly at enormous scales, and it can carry relatively large payloads. So far, we’ve administered it to animals for over a year without any detectable immunogenicity, and it is well tolerated at doses that are two orders of magnitude higher than traditional LNPs.

WuXi: What are your major regulatory and commercial challenges? What lessons have you learned?

Matthew Scholz: We’re pioneering a new class of treatment, and with that, we need to go above and beyond when it comes to demonstrating safety and specificity. It’s early days in the regulatory process of course, but we’re putting a lot of emphasis on those two points.

On the commercial side, we’ve needed to educate our audiences on the fact that this is a unique approach to targeting and delivery with an LNP, and that we’re distinct from past LNP approaches that have had their setbacks. In this respect we’ve already started to see progress with a compelling set of data and taking the time to walk people through the merits of the approach.

WuXi: As with other new medicines, the prices for some gene therapies generate “sticker-shock” among patients. Will gene therapies be widely accessible for patients? What changes are needed to ensure universal accessibility to these potential disease cures?

Matthew Scholz: I’m optimistic that as the industry works through the manufacturing and delivery issues, the costs will come down. In just the last decade we’ve actually seen a tremendous increase in the scale at which these treatments can be produced. As these therapies continue to target diseases with ever-larger patient populations, economies of scale will help drive down costs. Some of the technologies in use today might also simply need to be replaced with next generation versions before gene therapies can be widely accessible, much like vacuum tubes had to be replaced with transistors before computational technologies could be made widely available. Gene therapies won’t ever be as cheap as aspirin, but I do think they will become widely accessible.

WuXi: In general, what are the top 3 impediments to delivery of better medicines, faster and cheaper to patients?

Matthew Scholz: I’d say first of all is the science itself – there is a lot we don’t know about biology, and it takes a lot of time and resources to create a better medicine in the first place.

Second, in gene therapy specifically, we’re also quite limited by the technology: culturing patient cells and growing viruses involves processes and equipment that are clumsy, mostly manual, and nowhere near as mature as say the semiconductor industry.

And finally, the entire medical system seems optimized to do the exact opposite of “better, cheaper, faster.” From a regulatory perspective we prioritize safety of medicines over speed to market or cost – especially with new classes of treatments. People may argue over this balance that the regulators have struck in mitigating the dangers of drugs versus the affliction of disease, and I do think the system is delivering progressively better medicines, but I think everyone would agree that the current process is slow and exceedingly expensive.

Furthermore, patients, the ones who care most about these goals, have little to no influence over the system, and have to navigate layers and layers of bureaucracy, from the payors and benefit managers to the provider institutions themselves. The science and technology will continue to improve, but other key components of the healthcare system will need to evolve as well to truly make good on those advancements.