As a quick aside everything appears to be on its its way to a good resolution in my discussions with the government. Apologize for making too much of it was a bit of the standard government SNAFU situation. With that little bit of good news out of the way …
There have been some recent write-ups, (Gene therapy helps counter hemophilia B, ASH:Gene Therapy Puts Merry in ‘Christmas’ Bleeding Disease) about a new gene therapy treatment for a particular rare disease known as Hemophilia B, or Christmas Disease. The findings were formally published just this past month in the New England Journal of Medicine. This particular subtype of hemophilia is perhaps best known historically for having disproportionately affected the English aristocracy and notably affecting the son of Czar Nicholas of Russia. It is caused by an inability to make Factor IV in the blood, one of a number of enzymes involved in the coagulation cascade which allows blood to clot normally.
Archibold Garrod around the 1920s was the first one to start to write of what he termed “inborn errors of metabolism” where some key piece of the metabolic machinery is absent from birth. We would now also term these inborn errors of metabolism a subset of genetic diseases and a subset that comprises many of the most rare, serious and tragic of genetic diseases; ones which often lead to death in childhood. Hemophilia B is not an exception as the affected is always as risk of hemorrhaging to death from even minor trauma.
There are two ways at the present time we would look in conventional medicine to try and treat the root cause of these diseases. The first would be to replace the enzyme that is missing in metabolism. The most well known example of this is insulin replacement therapy in those with type I and some with type II diabetes, though type II diabetes is really an acquired not inborn metabolic problem. So at first tremendous expense and effort was made to carefully extract a small amount of insulin from say pig or cow sources. With the improved understanding of genetics it was subsequently learned how to take a simple bacterium, insert the gene for human insulin into the bacterium and soon have bacteria merrily churning out human insulin. This is the first, best known and still most widely used of the class of therapies known as transgenic enzyme replacement therapies. This is the approach used to treat Hemophilia B at the present, inject bacterially derived human factor IX. While it is a great advance there are limitations and problems with the approach which might take a page or so adequately discuss.
The other idea would be to see if you could correct the genetic blue print itself in the same way that a bacterial genome was altered. At first glance this looks like an ideal, straightforward and even simple approach. On paper this also looks simple in that bacteria will generate large amounts of foreign protein while a small change is all that is needed for human metabolism to normalize. Human physiology is very forgiving as regards enzyme function. With a whole organ system like lungs or kidneys there is a lot of leeway one needs to get below 50% functioning and really often down to below 30% functioning before one is in serious trouble. With enzymes there is even a far greater level of safety. One has to get down to below 10% functioning before there is a usually a noticeable problem and really down to 5 or 3 % before one has serious, life threatening disease. With how well things went with bacteria, you just need a small effect to correct the human inborn errors of metabolism. So in the late 1980s and early 1990s there was tremendous enthusiasm for gene therapy with the thought that genetic diseases might be a thing of the past. History has shown that it isn’t so simple and we don’t know as much as we thought. To date there has not yet been a single successful definitive gene therapy, and this most recent study is quite notable in that it may be the first.
While I am tremendously thankful for this wonderful advance in treating a tragic and life threatening disease which causes so much suffering to patients and families, there is still reason to be only cautiously optimistic and even to wonder if such a technology were mastered would it always be put to such necessary uses. As regards the second point, one might look at what I learned with my recent review of Marie-Monique Robbins excellent and spot on book, “Die, Monsanto Die!!!” er … rather “The World According to Monsanto”.
As an aside I don’t want to get off track on a technical discussion of different gene insertion approaches or gene modification in bacteria versus plants versus humans just to point out it occurred to me that Monsanto is altering the germ cell line of plants, something ethically outrageous and practically speaking, seriously dangerous. It is not at all the same thing as altering the somatic cell line in a single seriously ill human patient. This approach technically is also why they are able to have a measure of “success”. If you shoot ten thousand seeds with a gene gun and one survives you are on your way, however, you can’t kill 99.9% of your patients in a gene therapy trial. Again, as regards gene modification in higher organisms we still really don’t have a clue what is going on.
The approach used in clinical human trials to try and change the genome involves using a virus to carry the new gene as a payload and hope it inserts itself into the genome. So as regards the second point I made a while back about being cautious with these results, for one this study was only in six patients with a, at this point short term, increase in enzyme function of, if memory serves to 3-11%. There have been a number of times in the past that it also appeared a gene therapy was successful only to not turn out so.
One was the treatment of a small number of patients with the disease Severe Combined Immunodeficiency of the adenosine deaminase deficiency type, one of the “boy in the bubble” immunodeficiency syndromes. While the treatment was initially successful, about half, from memory, of the treated patients went on to rapidly develop a specific rare type of serious leukemia. It was later concluded that the particular virus used to deliver the gene most likely had a propensity to insert itself into a particular area of the DNA that would cause this cancer.
Even more concerning and tragic was the case of 18 year old Jesse Gelsinger. Mr Gelsinger suffered from a moderate case of a genetic disease known as ornithine decarboxylase deficiency. This gene therapy study was funded in part by the Office of Orphan Products while I worked there and though I was not directly involved I did encounter data, clinical records, photos and hear the opinion of pathologists and other experts. In essence all of his major organ systems melted over about three days after receiving the treatment. As far as I can tell no one knows what the hell happened. It was classified as a massive systemic immune response. This is also notable because the viral “vector” used to deliver the gene was a modified adenovirus. So just as viruses will recombine with human DNA they are also quite promiscuous in recombining with each other, hence the attempt to match the influenza vaccine to the strain that has arisen that year. It is both a theoretical and experimentally documented concern that genetically modified viruses can revert through recombination to the “wild” type strain. Adenovirus is better known as the most frequent cause of the common cold. Seeing as the cause of death was not clear, one can not help but speculate what could have possibly happened if Mr Gelsinger had had a cold at the time of his treatment. While it is science fiction like, again no one obviously enough knew what they were doing, and there is certainly a theoretical concern that you could have ended up with a pathogen that spreads as easily as the common cold and kills in three days from multi-organ system failure. Damn it, I started out so cheery and optimistic! Anyways that one shut down all gene research in the country for a few months. In this new hemophilia study though they are not using an adenoviral vector, they are using an adeno-associated viral vector, whew, no worries eh?
So where does this leave me? I am delighted that there may, possibly, be a start towards a new way to treat an awful and tragic disease. If by chance we master such a technique I sure hope we know how best to use it, you know use it to treat others as we would want to be treated ourselves, the Golden Rule isn’t it called? Now didn’t I hear some physician or maybe “politician” talking about something like that the other day?