As a longtime advocate for curing all bleeding and clotting disorders (for the sake of this article I will be limiting myself to hemophilia B), I have started wondering if we have spent enough time thinking about the next steps as we are moving into the age of gene therapy becoming a reality. I first want to define what I think a cure is for you. I have always defined it as a single treatment that provides the coagulation factor the person needs to a level that would fall within the normal range when tested for periodically over the life of the person being treated. In other words, a once and you are done forever, vision of a cure. Given where treatment started for me, I could make the case that treatment today might seem like a cure with the availability of long lasting clotting factors and prophylaxis treatments. But it surely does not meet the first criteria of a cure, that being a single treatment.
But, now we have the promise of gene therapy where a single treatment gives the patient the ability to produce the clotting factor themselves. There are several outstanding questions to be answered by way of clinical trials. They are all important questions to be answered but several stand out if this is to meet my definition of a cure. The first is the level of Factor IX to be produced and the other is persistence of that level. Please do not get me wrong on these points, if gene therapy can move a person from severe hemophilia B to a level where they are considered to have mild hemophilia B and the level persist for years, this would be a great step forward. I am only noting that it does not meet the standard of a cure that I previously defined and only time will answer the persistence question. If persistence of the clotting factor is not forever, then what is the possibility or probability of there being another vector available for gene insertion (note: the term vector is used to define a virus that has been hallowed out of its normal internal biology to carry new cell instructions to produce the clotting factor in a cell, currently liver cells are targeted by these viruses. Once used the body's immune system prevents additional uses of the same virus). All of these issues and points have been thought about and discussed for several years now. But there are several questions that do not get asked or discussed with any frequency which is the topic of this blog.
The first concern is the possibility that not everyone who is treated with gene therapy will achieve factor levels in the normal clotting range. As noted before moving someone from the severe form of hemophilia to the mild form, (which is only a function of the percentage of clotting factor in their blood) would be a huge step forward in treatment. But what if this advance could also imperial that individual in the long term? We as a community have invested years of teaching people about hemophilia and how to advocate for their needs in a medical setting like the Emergency Room (ER). We know from this long record that people with mild hemophilia are the hardest to reach because some do not know they have hemophilia, because they never had a problem. If they do know most of them do not understand just how serious it can be for them in an ER because they do not have a problem with hemophilia day to day. So let's say we treat a child at age five who was born with severe hemophilia with gene therapy and they get a result of a 40 % Factor IX level, which is good but not in the normal range, so they would have mild hemophilia by definition. They never have another issue until a car accident sends them to the ER at age 20, do we think that this person would have any understanding of what hemophilia is, and what their health care needs might be at that moment? We know today that the people born with mild hemophilia are more likely to have a very negative outcome even death when compared to their peers born with severe hemophilia in an ER setting. This is just a function of having the right information and sharing it with the medical professionals. It is the knowing how and what to advocate for at that moment that can be determinate of the outcome. Are we prepared to keep the educational efforts going over those fifteen years for people who may not really see the need for keeping informed about hemophilia. The reality is that even with a robust educational program we will see people that had severe hemophilia die with mild hemophilia because of a lack of knowledge and are we prepared to face that fact? I would hope the answer to that question is no. So the question is how do we continue to provide the educational sessions to a community that might not see the need to remain a community day to day unlike now where there is a strong community. We actually had this event where the hemophilia community was strong and active until the introduction of clotting factor and the "golden age of hemophilia" occurred, then we saw strong chapter organizations become a shell of themselves because no one saw the need. That is until the early 1980 when HIV/AIDS woke us up to the fact that we continually need to participate, educate and advocate for our own needs.
The next concern is generational, given the genetic probability that each child born to a carrier of hemophilia has a 50/50 chance to either have hemophilia if they are male or to be a carrier if they are female. All female children of a hemophiliac males will be carriers themselves. It may be necessary to setup a genetic registry to be passed from generation to generation about hemophilia in the family as we move towards a cure. We know today that about 30-35% of all new diagnosis's claim no family history and some additional testing shows some are new mutations either to the child or the mother. However, we also know that hemophilia can be hidden in a string of carriers across several generations before a male shows up with hemophilia, strictly because of the probability factor. In my own family there is a history but it jumped one generation even though there were two males born to a carrier, neither have hemophilia. If it had gone one more generation the possibility of anyone knowing the history would have been very remote. Regardless of the factor levels produced by gene therapy the underlying genetics of the individual will not have changed so we may see more carrier offspring of men who had hemophilia than in past generations. Due mostly to improved treatments and hopefully avoidance of medical mishaps like HIV. Most will live a coagulation normal life and may not have any understanding of what he is passing on to his daughters, because he himself may well not have the information of what it is to be a person with severe hemophilia.
The final question is persistence of gene therapy and this maybe a question that only time will answer. How long will gene therapy persist in the body, years, decades or forever? We know today that the liver can heal itself over time after an infection like Hepatitis C is treated and cured if the damage is not to extensive. So using this information and hypothesizing that liver cells infected by the gene therapy vector may well decrease over time causing a slow return to the previously normal level of clotting factor, in my case that would be less than 1%. Which would mean a slow return to having a severe form of the clotting disorder if no alternate vectors are available. So how do we prepare for this possibility, where someone returns to being severe after years of not needing treatment? Will we still have current day treatment available in that future after decades of not needing them? Will the educational programs and the foundations that provide them today still be around to inform them about their hemophilia if this possibility should occur? How do we prepare for something that might not occur but if it does could be a real problem for everyone affected.
I want to be clear, I am not diminishing the effect or casting doubt on gene therapy as a treatment, to the contrary I have tried to get into several research programs for gene therapy because I think it is important to find the answers to some of these questions for future members of the hemophilia community. I also do not want to see some of the same mistake made in the past repeated because we see a bright new future without hemophilia. I recently started to wonder what happens to our Hemophilia Treatment Centers (HTC) when we have a bunch of mild hemophiliac running around that do not have problems day to day for years but might well need their expertise in some future life-threatening event. If we as a community do not see their value to us under this premise, than how do we plan to maintain them over time for the eventuality that we do need them? I do not have all or any of the answers to these questions. But I think it is important to start to ask them so we as a community can have a conversations about planning for this future.