'Different Flavors' of Gene Editing Moving Closer to Your Clinic

This transcript has been edited for clarity.

Caron Jacobson, MD, MMSc: I'm Caron Jacobson, an assistant professor of medicine and the medical director of the Immune Effector Cell Therapy Program at the Dana-Farber Cancer Institute. Joining me today is Cathy Wu, a professor of medicine and the chief of the Division of Stem Cell Transplantation and Cellular Therapies at Dana-Farber.

Cathy, you chaired a session at the recent American Society of Hematology annual meeting that went into the breadth and depth of gene editing technology, thinking about the propelling of cellular therapies, and gene editing and genetic therapies for genetically inherited diseases. Can you give us some background about what gene editing is, how it's done, and what some of the methods are?

Catherine J. Wu, MD: From the very beginning, knowing that all of these diseases have at the basis some fundamental aberration in their DNA has always raised the question of whether we can correct it, and if so, how? Can we correct a condition, or can we replace something that should not be there? Blood disorders in general, both malignant and nonmalignant, have been "model diseases" at some level because we've understood very well that alterations are mechanistically and fundamentally the reason why they are there. Sickle cell anemia and alpha and beta thalassemia are examples. It has been super-exciting over the past decade to recognize that fundamental elements have the ability to track to specific regions in the DNA and guide the cutting or the replacement of certain nucleotide bases, making that correction or altering genes that might regulate expression of that region.

All of that technology now has come of age. We have these tools. One general category is CRISPR editing, and we've gone past proof of concept now to many different flavors of CRISPR editing that can happen both at the DNA level and the RNA level. It's worked its way into the research world where it's been an engine of discovery and the clinical arena, where now there are clinical trials and testing.

Jacobson: CRISPR, for example, was discovered in bacteria. It's a bacterial defense mechanism against other pathogens infecting the bacteria, which is amazing. So in trying to understand how bacteria evolve and protect themselves, we identified this new system that we can use in human cells.

Wu: It's a fascinating story about how some of the fundamental biology that we learned from plant biology has direct implications on how we can treat human disease.

Jacobson: It brings us back to things we learned in grade school biology. It all has implications for much bigger things later on.

Gene Editing Technologies

Jacobson: Let's talk about CRISPR and some of the other gene editing technologies. How are they being used in human therapeutic trials at this point?

Wu: Currently, studies are ongoing to address sickle cell disease. One approach is to change the expression of an element that controls expression of hemoglobin F. It's not correcting the sickle mutation, but rather altering the balance of hemoglobin so that the manifestations of sickle cell are not apparent anymore.

Jacobson: Is it a repeated therapy, then? Or are they targeting a stem cell in that case? How are they thinking about doing this in sickle cell?

Wu: I believe it's in the stem cells and then it's being engrafted. The other area is doing CRISPR editing in T cells for CAR T-cell therapy for treatment of cancer.

Jacobson: Most of the CAR T cells that we have seen in clinical development have been from the patient's own T cells. They don't have the risk of graft-versus-host disease because they are genetically similar or the same as the patient. But people are moving past that and wondering whether we can use healthy donor T cells. But if we keep that T-cell receptor in, then those T cells can cause graft-versus-host disease. A number of companies are using different gene editing technologies to get out that T-cell receptor.

Wu: One of the challenges with CAR T cells is how to make the manufacture more streamlined so that we can address more patients. One direction is to create third-party T cells. And there, the editing is really helpful in trying to adjust that third-party T cell so that it can be used.

Jacobson: There are people using them to adjust autologous T cells as well because we're learning about different immunomodulatory genes that are affecting the efficacy of CAR T cells. People are using things like CRISPR to knock out genes to prevent T-cell exhaustion, for example.

Wu: Exactly. We're learning more and more about what ingredients are needed to be present for CAR T-cell therapy to work most effectively. That is at the level of the receptor itself. It's also at the level of modulatory molecules and at the level of expression of different features that can modulate the activity.

Jacobson: And even the trafficking, right? That may help us break into solid tumors, which is the sort of glass ceiling at this point. Different companies are sort of attached to different methods of gene editing, like TALEN, ARCUS, and CRISPR. Are any of the processes different in your mind?

Wu: It's a calculus, right? It depends on the payload size and the efficiency of delivery. It depends on what cell you are editing. All of those factors have to be taken into account, and there are pluses and minuses with each technology.

Gene Editing for Other Diseases

Jacobson: Is there a role for this in treating nonmalignant, noncancer, nonhematologic diseases? What are some of the ones that might be next on the horizon?

Wu: Diseases that are related to a mutation or alteration that perhaps also have some lineage-restricted expression are actually quite amendable. For example, one could think of cystic fibrosis or Huntington disease. Those are all attractive opportunities in the future. We do need the first proof of concept. Again, the hemoglobinopathies have been a great first step out the door, but we can expect much more in the future.

Jacobson: When thinking about something like cystic fibrosis or Huntington disease, is it the same kind of concept? These are diseases that, once embryonic development is complete, it's hard to intervene because some of the damage is done. Is there a way to intervene early enough?

Wu: Conceptually, yes. As in any of these diseases that affect younger patients, we have to learn more about the safety profile. A robust discussion is ongoing about whether off-target effects are there or not. It's still a young technology, especially in the realm of clinical trials, so we have to wait and learn.

Jacobson: It makes total sense. CRISPR made its way into the media when there were some reports of embryos being genetically altered using this technology and the concern for regulation. Any thoughts?

Wu: It's a brave new world. I think that was a very impulsive moment. We always have to keep the ramifications of these new technologies in mind.

Jacobson: And we have to think globally, right? Because what we can regulate in one country may not be the same as what is being regulated in another.

That was very informative. Is there anything else you want the audience to know about these gene editing technologies and their prominence?

Wu: It's exciting. Keep your ears and eyes open because it's a very optimistic time. We should be seeing lots of exciting developments in the time to come.

Caron Jacobson is an assistant professor of medicine and the medical director of the Immune Effector Cell Therapy Program at the Dana-Farber Cancer Institute.

Cathy Wu is a professor of medicine and chief of the Division of Stem Cell Transplantation and Cellular Therapies at Dana-Farber.

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