Can Gene Therapy Work – Part II

Part I discussed the general subject of gene therapy including the pros and cons. In today's article, I will focus on the possible application of gene therapy as a treatment for Kennedy's Disease.

Gene Therapy and Kennedy's Disease

Recently I received the following inquiry. "Please review the article in Quest Magazine on gene therapy success.  My husband and I have been wondering if gene therapy from a healthy relative could be a cure for SBMA."

I thought this would be an opportunity to learn more about the differences between using gene therapy to treat inclusion-body myositis (IBM) (no, not the computer company) and Kennedy's Disease. So, we asked Mr. Science (the biology professor and KDA board member) and, as usual, he came through for me (why didn't I have professors like him when I was in school).

"This is a very interesting study, and if true, demonstrates a new (at least to me) method of gene therapy.  I hope to have the full copy of the paper soon.  I have the abstract and found a bit of info on the disease referenced in the study, namely IBM.  From what I could gather, the inherited form of IBM is a recessive mutation of the GNE gene.  This suggests that the disease is due to the lack of the normal GNE protein.  The researchers injected a good copy of the gene and their technique allowed the cells to take up this good copy of the gene - and the cells apparently were rescued.  However, note that the report in Quest indicates that not all muscles were rescued.   

Now with regard to Kennedy's Disease, this does not have a simple answer.  The problem with those of us with Kennedy's Disease is NOT that we do not have the function of a particular protein (in our case, androgen receptor, i.e., AR), but that the form we have (that still works) has an additional property that kills nerve cells.  This is what the scientists mean as a 'gain of function' mutation. Thus simply giving the patients a good copy of the AR will not help.  The one we have works fine and since we did not remove it during the therapy, cells will now have two copies, one good (the one we added) and the original Kennedy's Disease one.  The cells will still make the Kennedy's Disease version and so the cells will still die even though they now also have a good copy.  In order to be sure that the technique would work, not only would the therapy have to add the 'good' version of the gene, but one also remove the Kennedy's Disease version - and no one knows how to do that.  It is possible, however, that the progression of Kennedy's Disease could be slowed down by gene therapy - but I do not think that it is known that this would occur. 

I am not sure if I explained that well - so let me use a bad analogy.  Imagine that the protein made by the Kennedy's Disease gene is a watchdog.  The normal watchdog only attacks strangers - that's its function.  Most genetic diseases are due to the lack of a protein so in this analogy, this would be as if we lacked a watchdog (like IBM is due to the lack of a protein).  To cure it, all we would have to do is replace it with a new dog (as they did with the gene in the article).  Now if your problem was that you had a watchdog that not only attacked strangers, but also attacked your family; then getting a new dog will not be helpful as you still have the super aggressive one.  It is necessary not only to add a new dog, but also to remove the old one. 

Kennedy's Disease is like the second scenario.  We need to remove the old form of the gene as well add a good one. 

I hope that this makes a bit of sense - the bottom line is that simply adding the 'normal' copy of the gene probably will not be very helpful.  And if it were, it is unlikely that it would have to come from a relative - most anyone's copy would do." 

I also asked a neurologist and researcher, Dr. Paul Taylor, for his thoughts on the subject.

"There are a few obstacles to this approach in Kennedy's Disease. First, the therapy described here is gene replacement therapy. In other words, this type of muscle disease is caused by a deficiency of the gene in question and the therapeutic strategy is to replace the missing gene. Kennedy's Disease is not caused by deficiency of a single gene; rather, it is caused by toxicity of the mutated gene. Second, the disease described here is primarily a problem in the muscle cells themselves. These are an easier target than motor neurons, which are believed to be the primary cell type affected in Kennedy's Disease. 

That said, it is possible that treating muscle may turn out to be beneficial in Kennedy's Disease even if muscle is not the primary tissue affected by the disease. Maria Pennuto's data published last year suggests that possibility. In that case, rather replacement of a deficient gene, Kennedy's Disease mice had benefit from a muscle-boosting gene called IGF-1. Furthermore, it may turn out that primary muscle involvement is more important than we previously thought (we are working on this presently) which would make muscle an even more important target." 

Like anything else with Kennedy's Disease (and my computer when it acts up), a simple fix will not solve the problem. Perhaps that is why we are so unique (and I say that in a most positive way).

I find it interesting that the subject of gene therapy causes such a dichotomy of opinion. How do you feel about gene therapy ... especially if it became a treatment for Kennedy's Disease?