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Q&A: The ethics of germline editing
May 2017
by Kelsey Kaustinen  |  Email the author


A recent report from the National Academy of Sciences and the National Academy of Medicine outlined the opinions of an international panel of ethicists that, assuming several criteria for safety and disease severity are met, clinical trials featuring germline genome editing could be allowable. (The report, “Human Genome Editing: Science, Ethics, and Governance,” is available at The study was funded by several organizations, including the Defense Advanced Research Projects Agency, the Greenwall Foundation, the John D. and Catherine T. MacArthur Foundation, U.S. Department of Health and Human Services, U.S. Food and Drug Administration and the Wellcome Trust, with support from the National Academies’ Presidents’ Circle Fund and the National Academy of Sciences W.K. Kellogg Foundation Fund.
Dr. Sam Falsetti, head of Medical Strategy and Product Innovation at Cambridge BioMarketing, speaks with us about the implications this report could have in the field of rare diseases and gives us a look at where things stand for CRISPR/Cas9 editing in both somatic cell and germline editing.
DDNews: In broad terms, what is the state of the industry for rare diseases today in terms of new growth or interest?
Sam Falsetti: There has been a lot of growth since I joined the industry. I started off in oncology and virology, focused on targeted therapies, drug discovery and development, and then commercialization. When I got into rare diseases about six years ago, there were a number of rare disease products on the market. The idea of “rare” or “orphan,” which is defined by regulators as 200,000 people or fewer in the United States [with a disease] is a pretty broad classification.
While I work in the broader categories, I also work in a subsegment called “ultra-orphan,” which is not a regulatory definition but an informal industry definition of fewer than 10,000 patients. There is a difference between “ultra-orphan” and “orphan,” with the unmet medical need of the former incredibly high. Industry focus has grown substantially in both categories, but most significantly in ultra-orphan, which was somewhat of a niche in the past. We saw BioMarin and Genzyme enter the market first, later followed by Alexion and Shire. Now there are many pharmaceutical companies in this category, all with programs focused on drug development and commercialization.
DDNews: How important is this new decision regarding gene editing for individuals with rare diseases?
Falsetti: It’s a really important report, but there are a few things that have to happen for it to really resonate in the United States from an FDA perspective. The National Academy of Sciences (NAS)/National Academy of Medicine (NAM) report examines the new targeted technology, CRISPR/Cas9, that enables you to edit the actual DNA within a cell. There are currently clinical trials ongoing for gene editing in somatic cell lines. This means if there is a defect in a gene, it must be in your whole body; however, it may only be expressed in your liver, for example. You could decide to use some of the available gene therapy vectors that are presently being used to insert new genes, or you could make the decision to deliver the CRISPR/Cas9 system into the cell and edit the gene directly, instead of creating a new functional copy. Fundamentally, there is not a massive ethical discrepancy between those two approaches. That said, there is certainly more known about one technology than the other, even if they use the same delivery mechanism.
This report talks not about somatic cell, but germline mutations. To address the latter, one must enter the embryo and edit that specific gene in-embryo so that the person who is born with it has a functionally normal genome, devoid of that mutation. This approach prevents a person from being born with a disease and then being treated. This is a pretty interesting take, and I found it telling that it was an international group of ethicists who wrote this report, not just a group from the United States. It is helpful that this group has weighed in on it, and there's a lot of credibility because it's from NAS/NAM, but I do not believe this report on its own has changed or altered the FDA position on this. There is an ongoing prohibition on the use of federal funds by the FDA to do basically any research in which a human embryo is intentionally created or modified to include a heritable genetic modification. What is spelled out under this [report] that is helpful is a set of criteria under which heritable germline editing could be permitted if the U.S. restrictions are allowed to expire.
It is essentially a set of criteria stating the following: if you have an untreatable, rare, serious genetic disorder; and if scientists know which gene causes your disorder; and if the way that scientists are editing the gene is not going to create a new sequence that has never been seen in humans before and will only create a normal version of the gene, then the NAS/NAM ethicists believe that it is ethically allowable to move forward with clinical trial development. This set of criteria represents potentially very big news when you think about it—80 percent of rare diseases are genetic diseases, most of which do not have a therapy; certainly most of them do not have a cure.
At the same time, I will say that it seems that very few individuals who are looking at gene editing right now from a human perspective are working on germline, as far as I know. It is not where people initially want to go, which is understandable from a safety perspective. It's definitely more challenging, and we already know a lot more about somatic delivery systems. [This decision] is very helpful, but you must temper that with a little bit of a reality check based on the perspective of the investor, and from clinical trials and development—that's not likely to be the first application of this technology.
DDNews: What are you most excited about with regard to this new option for addressing rare diseases?
Falsetti: I’m most excited about advances that have the potential for a durable, potentially curative action. We’ve already seen good long-term durability with a couple of gene therapies to date. When we start thinking about durability of response with a one-time administration of anything—whether that's gene therapy or CRISPR/Cas9 systems—in this disease category in particular, it is a great thing for patients. The challenge, particularly in non-single-payer–markets like the United States, are the commercial ramifications. How do you price a one-time therapy that's going to deliver a massive value to the healthcare system (probably measured in millions of dollars) and to the patient and the family? These therapies could be the difference between having a severe disease and having a less severe version or no disease at all. Whichever range of improvement it is that you see, it will be challenging to develop a pricing structure against that.
In a non-single-payer market, it is incredibly challenging. If you're looking at it from an insurance company's terms, then you as a payer will pay for a lifetime of healthcare benefit for a beneficiary who may only be on your plan for a short time. Regardless of the time period, you will bear the full burden of that cost. In single-payer markets, financial and healthcare models are built in a way so we can evaluate the simple idea of saving someone's life, not just the intrinsic value of a life and the ethical considerations of that. These models can also look at it from a health economics perspective, imagining that a particular patient is someone who will be a contributor to society, who will work, pay taxes, and who will not be dependent on a raft of medical services.
DDNews: If the kind of germline editing discussed in the paper does someday get ethical and regulatory approval, what rare diseases might be easiest to target?
Falsetti: If you were to pursue a specific disease, you would first want to look for those that are incredibly severe and genetic in nature. It would have to be a monogenic disease, in which there is a very clear attribution to a specific gene defect. From a gene-editing perspective, you are working to edit the gene, not replace it. You should not look for genes in which there are chromosomal translocations, whole-scale gene deletions, or genes with large-scale DNA rearrangements. You are seeking genes that have a point mutation, compromising the function of the gene and turning it into a very impaired or null gene.
The challenge is that you could clearly develop a list of genetic criteria to create that need; however, theoretically you likely already know that an embryo has a genetic mutation. Particularly in the United States, people will screen different embryos prior to implantation to try and sort through the embryos that do not have a particular mutation. This is fairly common with people who know they have a genetic mutation, or a genetic disease in their family that's very severe. Genetic counselors put a lot of time into those types of situations.
Coming up with a disease and a clinical trial to test genetic intervention in a reasonable time frame with appropriate follow-up is a very, very large hurdle. We cannot be sure how that is going to proceed or what the commercial and clinical development framework for that would look like from a company and biotech perspective. It is interesting, and I almost wonder if that's more in the realm of academic groups, because it might align a bit more with what they might be looking to do from a timeline perspective and a scientific discovery perspective. However, to make a vector that would be suitable for that and have it characterized enough, I think that you would need more rigor that's better suited for industry than academia, having worked in academic drug development before. It's a tough set of criteria to get your head around.

Sam Falsetti, Ph.D., has been part of the Cambridge BioMarketing team since 2011, having previously served as the company's clinical science director, and brings with him more than 10 years of experience in drug discovery, development and medical communications. Falsetti has also served as a Data Monitoring Committee member for the National Cancer Institute’s Community Clinical Oncology Program for the last nine years.
Code: E051735



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