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Optimism Versus Reality

November 11, 2021

Not Mutually Exclusive for Our Patients

Patrick Ellsworth, MD

Dr. Patrick Ellsworth (@PEllsworthMD) is an Assistant Professor of Medicine in the Division of Hematology at the University of North Carolina at Chapel Hill. He specializes in adult and pediatric hematology with interests in nonmalignant hematology, especially sickle cell disease and bleeding disorders. His research interest lies in the interaction of endothelium with blood cells via coagulation proteins. Dr. Ellsworth hails from lovely Salmon, Idaho, and currently calls Cary, North Carolina, part of the famous Research Triangle, his home. Outside of his rigorous efforts to treat patients with nonmalignant blood diseases, Dr. Ellsworth enjoys hanging out with his wife and four children. 

Patrick Ellsworth, MD

My patients don’t want to be cured. There, I said it. In my clinic, I primarily see older teens and young adults with sickle cell disease. We spend much of their visits discussing how to enter adulthood with a genetic disease that has hardened many of them, leaving them by turns cynical, discouraged, and skeptical; they are also bold, strong, and hopeful. But they aren’t asking me to cure them. So why am I excited to see a panel (live Q&A taking place Saturday, December 11, 4:00-4:45 p.m. and including Drs. Paula Rio, Punam Malik, David Liu, and Nicole Gaudelli) discuss recent advances in gene editing for inherited blood disorders? 

About that first sentence: While factual (I haven’t had a patient ask me to “cure” them), curing sickle cell disease is conceptually foreign to a generation of soon-to-be adults who have accepted their disease as an inexorable part of themselves, to say nothing of their skepticism of a health care system that has long ignored their needs. They also read and hear that gene therapy is a complicated, messy proposition, with recent data showing concerning rates of myelodysplasia and leukemia in sickle cell trial participants. But as many dedicated clinicians and scientists work toward an effective, safe, and affordable cure with less toxicity and more universal availability than allogeneic transplantation, the landscape is changing. 

Beta hemoglobinopathies are the most common monogenic disorders in the world. As monogenic disorders, they in theory lend themselves quite well to a genetic cure. At this year’s joint session, we have the chance to hear from a handful of the world’s experts in the field of gene editing, with the topics substantively addressing hemoglobinopathies such as sickle cell disease and thalassemia, as well as other blood disorders. 

Several trials have been, or are currently, evaluating the use of lentiviral gene integration and CRISPR/cas9 editing techniques in hemoglobinopathies. Early data show that outcomes in hemoglobinopathy gene therapy are greatly affected by (among other factors) the efficiency of the gene editing itself, or to what degree all the hematopoietic stem and progenitor cells (HPSCs) have the gene in question repaired. This process is impaired by high numbers of double-stranded DNA breaks (a result of CRISPR/Cas9 use), and there is growing interest in enhancing precision to avoid these breaks and improve efficiency of gene editing, thereby augmenting the efficacy of the therapy itself. 

The presenters in this joint session will offer insight into promising new gene editing tools and strategies. Dr. Rio will discuss the “expanding toolbox” available to scientists seeking to advance curative therapies while limiting double-stranded DNA breaks. Dr. Malik will discuss strategies in development to improve the efficiency of homology directed repair, an inherent cellular mechanism that repairs the double-stranded DNA lesions at the core of CRISPR/Cas9 techniques. Dr. Liu will be discussing the use of cytosine and adenine base editors (ABEs), proteins that allow the change of point mutations without creating a double-stranded DNA break. Wrapping up the session, Dr. Gaudelli will expand on the topic of ABEs for hemoglobinopathies, including upregulation of hemoglobin F and β globin gene repair. 

A challenge with any therapy is the effective delivery to those who need it. With curative therapies, that delivery becomes even more fraught and resource-intensive. The advancing science of gene editing efficiency, while just a part of the whole process, is key to that effective delivery. After all, any discussion of curative therapy for hemoglobinopathies must orient itself in the bigger picture of how to make such treatments available to the millions of affected patients worldwide. 

My boss and colleague, Dr. Jane Little, has an analogy that I’ll paraphrase: Imagine everyone with a hemoglobinopathy is deserted on an island. If the New York Times’ coverage of gene therapy is any indication, many folks imagine gene therapy as a cruise ship coming to pick up a slew of passengers as quickly as they can board. In reality, gene therapy is more of a dinghy with an outboard engine, coming to pick up two or three people at a time. Also, there’s not even a nice dock built for those few to get on the boat. So where does this joint session fit? I see these scientists’ efforts as making a bigger, more comfortable, faster boat to rescue our patients stranded on dry land. The dock and tickets to ride are equally important issues, but we have to start somewhere. 

With all the work being done to make these therapies available, efficient, and safe for all those affected by inherited blood disorders, we can look forward to a discussion of barriers and proposed solutions to the gene editing process and the promise it holds for these patients. In addition to updates on gene editing itself, I will personally be looking forward to a discussion of how these techniques might impact the delivery of these therapies and the implications for future iterations of curative therapies. 

So, should hematologists be optimistic or realistic about the technologies underlying current and future gene therapy? I suggest we follow our patients’ lead on this one. Even when (as I’ve often found) patients aren’t personally seeking curative therapies, they want to know about advances in the field, regardless of whether they stand to immediately benefit. Knowing that a cure may be available, even to a relative, has my patients excited. It’s the striving that resonates with them. In short, we can be optimistic and realistic. And with advances that will inevitably make therapies based on gene editing a safer, more reliable, and cost-effective reality for patients, I believe I’ll have patients routinely asking me for a cure before I’ve retired. 

Dr. Ellsworth indicated no relevant conflicts of interest. 

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