QOTW “Any progress in gene therapy for HAE?”

Feb 22, 2016

Dr. C: This is at the heart of what our future hope is for HAE—a cure. For HAE type I and II with well-characterized mutations linked to the disease, gene therapy is a topic of great interest. In the past attempts to deliver “good” genes to cure disease have worked in a few instances but have also resulted serious complications such as malignancies thereby limiting enthusiasm. New technology has emerged however in gene editing that may provide a pathway. CRISPR-Cas9 was first reported 3 years ago, with this technique the “bad” part of the gene can be edited out. Much like the old film strips where a scene was cut the film spiced back together. This process now allows scientists to make specific changes to specific genes in living cells. For HAE type I and II this could conceptually allow repair of the defective gene. We do need clarity for HAE nl C1 inhibitor patients on the genetic basis for disease prior to this being universally applicable for HAE.
There have been lots of ethical debates about what the new gene editing technique could do in a bad way—think Ninja mutant babies. We need to be very cautious with any new technology in particular where we have safe and effective therapies for treatment. In other words simply having the methods in our hands does not translate into a signal to proceed—we must be very careful. Bruce and Marc would you like to wade in on our reader’s question? How close are we to utilizing gene therapy for HAE?


Dr R: Since HAE due to C1INH deficiency (Types 1 and 2) is a genetic condition where the location (C1INH gene on Chromosome 11) and type of mutation can generally be mapped out by gene sequencing, the prospect of gene repair is attractive. Currently, a couple of therapeutic strategies might be capable of addressing the underlying gene mutation, thereby increasing C1INH production and theoretically curing the condition. One strategy for gene therapy is to “deliver” the normal functioning gene to the cells of the body using engineered viruses. These viruses (sometimes called vectors) are designed to be loaded with the desired genetic material needed to correct a disease and then infect human cells without causing damage or illness. This allows the normal gene delivered by the virus to eventually incorporate into the treated individual’s DNA and restore normal cell function, in this case, the production of C1INH protein. This approach has been used in a handful of genetic conditions, but not in HAE to date. Viral vector gene therapy has been successful in some diseases, but there have also been serious setbacks along the way including cancer caused by the inserted genetic material missing its target and having unwanted effects. Work continues to design safer and more effective viral vectors for this type of gene therapy. The other approach, which is newer, is gene editing. With gene editing, molecules called nucleases are engineered to cause breaks or nicks in the DNA strands at very specific sites targeted for revision or repair. These breaks are then used to “edit” the DNA at the site by replacing or reconstructing the gene to it’s normal functioning state. A few types of “molecular machinery” have been successful in accomplishing gene editing, though CRISPR technology has recently generated the most buzz in medicine. Gene editing appears very promising, but its use in humans is in the very early stages. There are also concerns about unknown or unexpected side effects from altering DNA in this fashion, so scientific and ethical guidelines have been established to try to prevent serious missteps or misuse of the technology. Within the next few years, I’m cautiously optimistic we’ll see clinical development of these gene therapies in numerous medical conditions, and hopefully HAE will be among those studied. Whether this will be curative for HAE is uncertain, but we’re moving closer to that possibility, with the caveat that there are a lot of unanswered questions to be addressed along the way.


Dr C: Thank you Marc. Bruce where to you think we are in this process?


Dr Z: I’ll take the contrarian approach here, even though we are working on gene therapy techniques for HAE in my laboratory. My sense is that we will soon have very effective long-term prophylaxis that will essentially stop attacks in HAE-C1INH patients. The same may be true for HAE-XII as well as other forms of HAE-nl-C1INH as we uncover the causes. My feeling is that once we have really good and convenient treatment for HAE, we ought to slow down and wait for gene therapy to mature before trying it in a disease that is otherwise controllable. As Hippocrates said almost 2,500 years ago: “Also I will, according to my ability and judgment, prescribe a regimen for the health of the sick; but I will utterly reject harm and mischief”. Until we know that we can carry out gene therapy in a safe and effective manner, lets’ concentrate on controlling HAE with effective medicines.


Dr. C: I agree, very exciting but “first do no harm”. Thank you Bruce and Marc—I hope that our discussion was helpful for our reader and followers with HAE. We look forward to hearing from you and our next “Question of the Week”.


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