Ionis and Roche (two pharma companies) issued a press release with regard to a clinical trial using antisense oligonucleotides (ASO) in Huntington Disease patients. ASO's are a treatment that attempts to reduce the amount of a mutant protein. In the case of HD, it specifically is meant to reduce the amount of a mutated protein called Huntingtin - a mutated version of this protein is the cause of HD. This was a phase 1 study meant to 1. determine safety, 2. determine if the treatment reduces the amount of the mutant protein in HD patients. The bottom line is that under the conditions of the study, the treatment was safe and it was successful at reducing the levels of HD protein. A very good review of this study can be found here here.

Why should you care? HD and KD are genetic cousins in the disease world. They each are caused by elongated CAG repeats in the affected gene, the Huntington gene for HD and the androgen receptor for KD. What this means is that there is no reason that effective ASO's cannot be developed for KD. I believe that Ionis is also working on an ASO for KD and ASO's have been effective in mouse models of KD. So this is a big deal.

Note, however, that the present study did NOT test for any improvement of symptoms - that will be a goal for the next stage (as described in the link I inserted above). This is, however, a great first step.

I wonder how this would work with KD. I assume all instances of our defective gene/protein has a purpose. If all defective genes are targeted by the ASO how is the original purpose of the gene fulfilled?

Awkward sentences but I think you can get the meaning.

Is it the case that only some of our subject genes are defective?

Or... "it specifically is meant to reduce the amount of a mutated protein called Huntingtin - a mutated version of this protein is the cause of HD" does the ASO kill all instances of Huntingtin protein, or can it detect the mutated protein? Do we have a similar case with KD?

Bob, you raise a good point. The Huntington's gene is on a chromosome that we get a copy of from each parent while men with KD only get 1 copy of the gene. Thus we only make mutant androgen receptor protein and blocking it with an ASO ought to have effects similar to drugs like dutasteride that reduce our already impaired androgen signaling. Gene therapy through a tool like CRISPR is likely a better approach but ASOs have been around longer and is likely to be available sooner as a therapy for KD.

Bob,

These are great points and certainly indicate that there are issues to be resolved before an effective treatment will be developed. As Todd mentions, gene editing (CRISPR/cas9) would be the ideal fix but there are important issues that also need to be resolved before a treatment could be implemented. I suspect that ASO's are more likely to be ready for testing before gene editing.

To address your questions, I suspect that there are two approaches that will try to minimize the effects of using ASO's to stop the synthesis of the AR:1. tissue selection: the ASO's must be delivered to the tissue and it is possible to use a procedure that, for example, only will deliver the ASO to the muscle cells (or conversely, nerve cells) - thus the effects of the lack of AR would only be observed in specific tissues. It remains to be seen if this is sufficient to alleviate the primary symptoms of KD. 2. I suspect that the goal of the ASO's is not to remove all the AR but to reduce it enough that the symptoms of KD are reduced but the AR can still do its normal function. If an ASO for KD is developed (and I think that one will be), the obvious goal of the initial clinical trials would be to determine the necessary conditions to be effective.