Therapeutic Gene Editing. A Lot Done, a Lot More to Do. Interview With Eric Kmiec, Ph.D.

(Interview is condensed and edited for clarity)

Karen - Eric, I'm absolutely delighted to have you with us today in the virtual studio.

Eric - Thanks, Karen. It's absolutely great to be here. Good afternoon and good morning to everyone, wherever you may be.

Approval of the first gene-editing therapeutic

Karen - Today, we're going to talk about therapeutic gene editing: a lot done and a lot more to do. Let’s start with what has been done. We saw the first regulatory approval for a gene-editing therapy with the approval of CASGEVY to Vertex Pharmaceuticals and CRISPR Therapeutics just before Christmas. As somebody who has worked in the gene-editing field for 25 years, what does this milestone mean to you?

Eric - I think, speaking for everyone who has been a part of this journey, that it is totally gratifying to see decades of interesting work at the bench coming to fruition. We are cheering this approval and future developments along quite strongly!

Karen - There's been a lot of hype in recent years about how fast the gene-editing field has moved. Since the first demonstration of CRISPR in eukaryotic cells 12 years ago, we've seen the Nobel prize being awarded for CRISPR, and more than 150 gene-editing clinical trials are now ongoing. In your opinion, has it really gone that fast, given that gene editing has been around for many years, and sickle cell disease was probably among the original targets?

Eric - Well, I'm living proof that it hasn't gone that fast!

Gene editing started off in lower eukaryotic model organisms, where people were able to generate genetic knockouts using viral vectors and DNA sequences. The hope was always that we would be able to achieve the efficiency needed to repair genes, but through the years, that became much more challenging, largely because earlier methods did not yield high levels of accuracy. With the evolution of programmable nucleases, starting with meganucleases in yeast, then zinc finger nucleases, TALENs and eventually CRISPR, those in the field started to believe that we could improve the precision and efficiency. For just about every form of major breakthrough in any field, there will be decades of work behind it.

Sickle cell disease was always a popular target, and Stuart Orkin’s work on understanding the globin locus and discovering that there was a repressor of foetal globin expression led to the evolution of what we see today with the approval of CASGEVY.

Karen - As many of our readers will know, the therapeutic strategy underlying CASGEVY does not involve correcting the mutations that cause sickle cell disease or beta thalassemia. Instead, and as you alluded to, CASGEVY is designed to reactivate the expression of foetal haemoglobin as a way to compensate for the lack of functional adult haemoglobin seen in those diseases. This strategy was shown to be efficacious in clinical trials of CASGEVY. What kind of other target would this approach be useful for in your opinion, and why not simply correct the mutated gene instead?

Eric - I’ll take that question in two parts.

First, in our lab we are advancing a similar approach in oncology. Chemotherapy resistance is generally controlled, at least partially, at the genetic level. By exploiting what CRISPR does naturally, i.e., cutting DNA, we can disable certain cancer-specific genes that are preventing available therapies from working effectively. We have demonstrated that this approach can augment the effect of standard-of-care chemotherapies so that lower doses can be given, and we see many more opportunities in this area.

Second, with regard to simply correcting mutated genes, our lab and many others have found that to be really challenging for numerous reasons, including the choice of vector to deliver CRISPR reagents to cells and lack of precision. The fact is that CRISPR naturally cuts DNA and we rely on the cellular DNA repair pathways to ‘do the rest’. I think there's some hope for precise gene correction now with prime editing and base editing because they don’t necessarily involve breakage of the DNA.

Where will therapeutic gene editing make the biggest impact?

Karen - It’s interesting to hear you speaking about cancer here, because much of the focus has been on the potential of CRISPR to cure rare diseases, many of which are completely untreatable. Despite the large number of ongoing trials and the first approval, I think we are still in the early days of gene-editing therapies. Where do you think therapeutic gene editing is likely to make the biggest impact?

Eric - I think it gives hope for people who have no hope. There are plenty of examples of inherited diseases for which pharmaceuticals have largely failed. For instance, many sickle cell disease patients receive hydroxyurea as a prescribed treatment, which is associated with severe side effects. I've always believed that regardless of the financial or scientific challenges and burdens that we face in developing these new types of drugs, that patient suffering counts. So, I think as humankind we have a responsibility to develop drugs to relieve that suffering, whether it's expensive or not.

At ChristianaCare, we believe that gene editing can make a huge impact in oncology. Cancer patients receiving chemotherapy or radiation must deal with serious side effects, and for those who are treated with immunotherapy, e.g., CAR T-cell therapy, the preparation needed can be significant in terms of immunosuppression, and the patient is often not left with much choice. So, to sum up, I think that gene editing gives hope where there has been no hope until now, but also provides an opportunity to break into some new approaches in cancer care.

Karen - I agree that there are many opportunities ahead, and it will also be interesting to see the impact of gene editing in the chronic disease space.

The cost of gene-editing therapy

Karen - Before we move on, I think it’s fair to mention that there have been three new approvals for sickle cell disease in the last few years, including a monoclonal antibody to reduce the number of pain crises, a small molecule drug that increases the affinity of haemoglobin for oxygen, and L-glutamine to combat oxidative stress. However, all of those therapies require frequent administration, either as pills or via injection, which puts a burden on the patient to regularly attend a clinic.

It’s clear that a one and done approach is much more attractive, but these are very expensive as you hinted earlier. CASGEVY and lovo-cel, which is the newly approved sickle cell disease gene therapy developed by bluebird bio are both coming in at over $2 million, and there is concern in the field about whether those treatments will ever get to the people who need them the most. So how do you think we can solve this cost issue, or is it eventually going to be detrimental to the field of genetic medicine?

Eric - There's no doubt that these prices are shocking to potential buyers. Our hope is that eventually, as in the case of immunotherapy and cell therapy, the cost will come down as it becomes easier to manufacture the necessary reagents. It's still very expensive to make biologics but there is a major emphasis within the industry and universities to improve bio-manufacturing.

One thing I have learned at ChristianaCare is the importance of patient-first strategies. It’s hard to put a cost on patient suffering and reducing that is crucial. So, while I understand the concerns about cost, I remain optimistic that at some point, the manufacturing costs of these gene-editing entities will be reduced. Sickle disease was an interesting choice to go with early on, because while it is a global disease, it’s a rampant problem in Africa. I think that the transition to where these new therapies will affect people in Africa and globally will be interesting to watch.

Karen - I think it's also important to point out that the current average lifetime cost to the healthcare system of treating a patient who has sickle cell disease or beta thalassemia is estimated to be between $4 and $6 million. This excludes the additional expenses incurred by the patient, e.g., travelling to the hospital, overnight stays in hotels and all the other costs that come with having a chronic illness that's probably poorly managed at best.

Delivery remains a bottleneck

Karen - It feels like we're moving into the ‘a lot more to do’ part of the discussion now! There are many things to discuss here, but I’d like to talk about the delivery issue. We've seen progress in recent years; we now have viral and non-viral approaches to choose from, some of which are already in the clinic, e.g., the lipid nanoparticles. But delivery still seems to be a major bottleneck, particularly for in vivo therapies that need to reach organs beyond the liver, and especially for very hard-to-reach organs like the brain, which is enclosed by the protective blood brain barrier. So, given that the delivery toolbox has gotten bigger in recent years, do you think that we currently have the solutions we need, or do we need to see even more new delivery modalities emerging?

Eric - We have lived through decades of viral vectors, and their success is undoubtable. However, one of the concerns with this approach is off-target mutagenesis. Constant expression of Cas protein and guide RNA increases the risk of cutting the chromosome at non-target sites, whereas a non-viral particle that delivers Cas9 mRNA and guide RNA allows transient editing. If the efficiency is high enough with non-viral methods, then we can avoid those secondary off-target events, so we have waited a long time for non-viral particles.

I think that the COVID-19 vaccine work has transformed gene editing because it has demonstrated the success of using a non-viral particle to transmit viral mRNA. As well as that, watching Intellia Therapeutics and Verve Therapeutics, both of which have been very successful in targeting liver-based diseases with lipid nanoparticles, has convinced us that the future is probably non-viral vectors. At ChristianaCare, we are mostly interested in localised delivery, whether that’s pumps for glioma, head and neck cancer or lung cancer, and we have also moved to non-viral approaches.

We are closely watching the advances being made with lipid nanoparticles, which are now being developed to target specific tissues. However, it’s not just arrival at the target tissue or organ that’s important, but also penetration into that tissue, especially when it comes to treating tumours. I am optimistic that lipid nanoparticles that are able to accumulate at and penetrate specific tumours or organs are on the horizon.

Karen - I think you are right to be optimistic. Verve Therapeutics is already starting a clinical trial with its in vivo base-editing candidate VERVE-102, which uses proprietary GalNAc-LNP delivery technology to specifically deliver a base editor to the liver via a liver-targeting ligand.

It will be interesting to see how delivery methods evolve as more in vivo candidates enter the clinic. I think that’s where we're really going to need differentiation when it comes to delivery; the vast majority of programmes in the clinic now are still based on ex vivo editing of cells.

Navigating the regulatory pathway to the clinic

Karen - Let’s shift track a little bit. Ultimately, the goal of any of the gene-editing companies out there, including CorriXR Therapeutics, is to bring new treatments to the market. How easy is that to do in a field that's still in its infancy, and given the fact that the long-term implications of editing the genome still remain unknown? In your opinion, are the regulatory bodies doing enough to guide prospective sponsors in this area?

Eric - I have enormous respect for the people who sit on those regulatory panels. We have carefully followed the discussions surrounding Vertex’ regulatory applications and with a great deal of admiration and respect, I would say that we're building the plane while we're flying it. I mean, we're kind of learning how to do this as we go along, and the regulatory agencies are providing great guidance.

What can be challenging for our regulatory agencies is that when a new technology emerges, particularly a new analytical tool in the DNA or RNA sequencing world, there tends to be a rush that everybody has to use that tool to confirm there's no off-target effects in their workflow. There’s a big difference in who can afford to do that, whether it’s a major pharma company or a smaller entity like CorriXR Therapeutics.

ChristianaCare has taught me a lot about combining gene editing with patient care, and sometimes the goal will ‘just’ be to advance progression-free survival of cancer patients for three to six to 12 months.

What I'm hoping for, and what we're also beginning to see at the US FDA that we deal with, is a tendency to look at therapeutic gene-editing strategies as unique protocols. We are interested in supporting progression-free survival in mid- to late-stage cancer patients, so off-target mutagenesis for those patients may not be as critical as for a child with sickle cell disease. This is why we chose to begin working with a patient group that has no option, but where we may be able to improve their quality of life in a serious way without having to worry about the long-term effects.

Karen -So perhaps the take-home message is that any company developing a gene-editing therapeutic should be engaging with the regulatory authorities early on to find out exactly what pre-clinical data will be needed because there is no one-size-fits-all approach. And perhaps we will see differential regulation, as we see already with small molecule drugs for cancer.

Eric - Absolutely. We hope that this shift in how the regulatory agencies look at gene-editing programmes will result in differential pathways to approval, depending on what the overall treatment goal is.

Karen - This has been a really interesting discussion, but we are almost out of time now. Thanks very much for sharing your insights with us today, Eric. I hope that you will come back and tell us more about CorriXR’s oncology programmes at a future CMN Live session. Until then, we look forward to meeting you at the CRISPR Med conference in Copenhagen this April!

Eric - Thank, Karen. This has been a great pleasure.

Relevant links

1. In Our Blood: A Profile of Stuart Orkin. A summary of the groundbreaking work led by Stuart Orkin MD (Professor of Pediatrics, Harvard Medical School), that advanced our understanding of the globin locus and led to the discovery of the foetal haemoglobin repressor, BCL11A.
2. Clinical Highlights From the Gene-Editing Field in 2023. End-of-year roundup from CRISPR Medicine News featuring the landmark approval of CASGEVY for sickle cell disease in November 2023, and Verve Therapeutic's VERVE-101 which is being evaluated in clinical trials for heterozygous familial hypercholesterolemia.
3. Gene-Editing Tools: Delivery Methods and Challenges. For this special article published in January 2024, CRISPR Medicine News interviewed multiple experts in gene editing about the advantages and limitations of different delivery methods, with a particular focus on non-viral methods.
4. CorriXR Therapeutics website.
5. ChristianaCare Gene Editing Institute website.

Selected publications from the ChristianaCare Gene Editing Institute

1. Banas K, Modarai S, Rivera-Torres N, Yoo BC, Bialk PA, Barrett C, Batish M, Kmiec EB. Exon skipping induced by CRISPR-directed gene editing regulates the response to chemotherapy in non-small cell lung carcinoma cells. Gene Ther. 2022 Jun;29(6):357-367.
2. Rivera-Torres N, Bialk P, Kmiec EB. CRISPR-Directed Gene Editing as a Method to Reduce Chemoresistance in Lung Cancer Cells. Methods Mol Biol. 2023;2660:263-271.