Many of you may have heard the exciting news on December 11, 2017 about a potential treatment for Huntington’s disease! If not; an Ionis Pharmaceuticals drug, HTTRx, has been shown to be well tolerated and exhibit dose dependent reduction of mHTT in a Phase 1/2a study that is ongoing at University College in London! This has lead Roche to exercise its option to license IONIS-HTTRx and Roche will now be responsible for the continued development which in the short term will include an open label extension of the study. This means that patients that received the placebo treatment will now be able to receive the drug because of the encouraging results seen thus far.
A LOT going on there! So let’s start with what is Huntington’s disease (HD) and what is known about how it is caused. Huntington’s disease is a rare genetic disorder that is characterized by unstoppable neuronal death which leads to permanent decline in movement and memory and eventually leads to death. The effects of Huntington’s are generally not seen until people are in their 30’s and 40’s and if an individual is found to have Huntington’s there is a 50% chance that each of their children will also succumb to the disease. Approximately, 30,000 people have symptomatic HD in the U.S. and the number that are at risk of having inherited HD is over 200,000.
It has been known for some time now that Huntington’s disease is caused by a mutation of the huntingtin gene, specifically a CAG expansion. Thus HD belongs to the family genetic diseases called triplet repeat disorders. This mutation is typically only seen in one of the 2 alleles for huntingtin so an individual with Huntington’s disease will actually express normal huntingtin (HTT) and mutant huntingtin (mHTT). This makes some sense since studies have shown that simply getting rid of the huntingtin gene is embryonic lethal in knockout mouse studies. Waiting to eliminate huntingtin until after birth resulted in mice that exhibit severe neuronal degeneration. This means that HTT has a role in normal development.
So, the goal should be to get rid of the only the mHTT right? Well, that is not so easy since mHTT is not identical in all of the affected individuals in fact a stretch of CAG repeats (of varying length) is normal and identifying and targeting every possible mutation would not be cost-effective. Fortunately the results of this, and previous, studies indicate that may not be necessary. You see HTTRx is not designed to bind and eliminate only mHTT. So what is HTTRx and how does it work?
HTTRx is an antisense oligonucleotide or ASO, one of several strategies that have been used for so-called gene silencing. In the case of HTTRx it is a single strand of modified DNA that is designed to stick to a sequence in the huntingtin mRNA. To design an antisense drug one first needs to have knowledge of the sequence for the mRNA that you want to eliminate. Ideally you want to find a sequence that is completely novel for this mRNA so you need to know the sequence of all of the other RNA’s. The modified oligonucleotide sequence is then designed to match this sequence creating a region of approximately 25 nucleotides where the mRNA is double stranded.
It is important to note that I said modified DNA. Since it is not normal for single stranded or short sequences of DNA to be floating around in a cell they are usually eliminated. Basically the oligonucleotide sequence will be broken into the individual bases by enzymes in the cell (endonucleases and exonucleases). This was realized early on in anti-sense research and a variety of chemically modified DNA bases have been tried to find ones that are not degraded in the cells and have the same base-pairing properties as their unmodified counterparts
Similar approaches using antisense RNA have also been used and when mRNA has a passenger such as this that makes a double stranded stretch in the mRNA it cannot be translated into a protein and/or is targeted for degradation. Either way the protein expression is reduced. In order to get to this stage HTTRx had to go through A LOT of testing to confirm specificity and that the results observed based on treatment with the ASO are due to its ability to reduce its target protein. Even though these gene silencing approaches are fairly simple in concept they have the potential for a variety of off-target effects that may not even be associated with a decrease in any protein expression.
So, HTTRx is really a huntingtin lowering drug and lowering huntingtin has been shown in mice to improve symptoms. Will HTTRx improve symptoms in humans? Right now that is hard to say. But these results are definitely a step in the right direction. They show that HTTRx can be used for lowering mHTT (and HTT) at doses that can be safely administered to humans. If mHTT can be maintained at a low level, the expectation is that the individuals enrolled who would normally succumb to Huntington’s disease will be spared from the fate that their parents suffered. The subjects of this study were just beginning to show symptoms of Huntington’s disease. For the first time they have hope! And more important for some their children may never need to suffer.
What do these results mean for other diseases? Well, another single gene disorder Pachyonychia Congentia could benefit from a similar approach. Will a similar approach that does not specifically target the mutant protein have efficacy in this disease? What about other neurodegenerative diseases? Even when a specific protein is implicated in the disease, such as synuclein in Parkinson’s, it appears that these diseases are more complex than HD. However, the idea that a gene that affects disease progression can now be modified is reason for excitement!
We look forward to the additional details about the results of this study which promise to be forthcoming in the new year!