Huntington’s disease is an inherited neurodegenerative disorder that leads to the progressive degeneration of nerve cells in the brain. The disease is genetic in nature and is caused by a toxic gain of function mutation in the huntingtin gene (Htt). In fact, the disease is an autosomal dominant disorder, where only a single copy of the defective gene is sufficient for development of Huntington’s. Unfortunately, there are no disease modifying drugs on the market and currently approved medications are simply used to redress the symptoms of the disease. In fact, most of the drugs used in Huntington’s disease are meant to limit the chorea (involuntary movements) associated with disease progression.
Despite the lack of disease modifying agents, the genetic basis of Huntington’s disease is relatively well understood. The huntingtin gene occupies a part of the chromosome where normal alleles contain a CAG repeat. In Huntington’s disease these CAG repeats occur in significantly larger numbers. Albin and Tagle (1995) noted that, “CAG-repeat range of normal chromosomes is 9-39 (mean 18-19 with the vast majority of chromosomes exhibiting repeat lengths shorter than 30), whereas HD chromosomes show repeat lengths of 36-121 (mean 42-46, with the vast majority of chromosomes exhibiting repeat lengths greater than 40).” In other words, for an individual without Huntington’s disease, the CAG repeats about 18-19 times, whereas those with the disease have repeats of greater than 40. The Huntington gene then produces both mutant Htt messenger RNA and normal Htt messenger RNA. The key for a disease modifying therapeutic would be to eliminate the mutant Htt messenger RNA, while leaving the normal Htt messenger RNA unchanged.
Sangamo Biosciences (NASDAQ:SGMO) announced positive pre-clinical data on October 17th that was presented at the 2012 Annual Meeting of Society for Neuroscience. Sangamo has developed a zinc finger DNA-binding protein (ZFP) that can silence the mutant part of the Huntington gene, while leaving the wild-type relatively unchanged (this product is part of a collaboration with Shire [NASDAQ:SHPG]). In fact, the press release provides a detailed, and quite positive, description of the data:
“In multiple independent cell lines derived from HD patients carrying different, disease-causing CAG repeat lengths, they demonstrated that these ZFP TFs decreased production of the mutant HTT messenger RNA (mRNA) by >90% while leaving the levels of the normal HTT mRNA largely unchanged (a reduction of 10% or less); in turn, this achieved similar selective reduction in levels of mutant compared to normal HTT protein. Furthermore, in neurons derived from a HD mouse model (R6/2), ZFP TFs selectively repressed the expression of mutant HTT, which is required for disease expression in these animals.”
In other words, the ZFP was able to virtually eliminate the mutant Htt mRNA, while leaving the wild type only slightly affected. In addition, the neuron results hint that this knockdown is sufficient to alter the course of the disease.
This is clearly an important development, but these results should be examined in the context of Alnylam’s (NASDAQ:ALNY) investigational disease modifying treatment for Huntington’s disease. On December 28th, 2011, Alnylam reported the publication of its pre-clinical data. Rather than use a ZFP, Alnylam utilizes a small interfering RNA (siRNA) to silence the huntington mRNA. The company reported that the treatment “resulted in the silencing of the huntington gene throughout the putamen by an average of approximately 45 percent, as well as reductions in the levels of huntingtin protein when evaluated by immunohistochemistry.” Stiles et al (2011) indicate that this 45% includes both the mutant Htt and wild type Htt but argue that, “it is anticipated based on these studies that partial Htt lowering (of both WT and mutant Htt) in the adult may be both safe and effective.” In other words, they do not see the additional suppression of normal Htt as being therapeutically problematic.
Alnylam and Sangamo are offering two different ways to create a disease modifying agent. Alnylam is using RNA interference (RNAi) to modify the expression of genes, whereas Sangamo is using zinc fingers DNA binding proteins (ZFP) to modify the expression. In many ways, Sangamo has the more flexible platform in that it works on the DNA and can delete parts of it, change parts of it, or modify its expression. Alnylam, on the hand, works downstream at the RNA and has no ability to directly alter the gene. The other advantage for Sangamo is in terms of delivery. It has proven more difficult that initially thought to get RNAi drugs delivered in sufficient amounts to actually modify the expression. This is especially true for neurological diseases as Stiles et al (2011) specifically note that “because of the blood–brain barrier, one of the major challenges in translating RNAi treatments into clinical treatments for neurodegenerative diseases is delivery.” For the Huntington’s disease non-primate trial, they had to use a convection enhanced delivery directly “into the non-human primate putamen” (Stiles et al 2011). Clearly that is not a practical delivery system for humans, although to be fair Sangamo data was on cell lines and not delivered into an animal. An earlier study, however, did deliver a ZFP into animals and achieved a decrease in mutant proteins and mRNA in the brain (up to 60%). That effect in the animal was achieved with a less efficient ZFP than that used in the recent research. As such, it looks like delivery will not be a major issue, and with the newer ZFP one would expect even better results than the previous animal models.
In general, Sangamo with its ZFN seems to have an advantage in delivery and a more flexible platform in that it can not only modify expression but also edit the gene. The Huntington’s disease data should be viewed not only as movement towards a disease modifying therapeutic agent but additional validation of the platform for the treatment of monogenic diseases. Outside of Huntington’s disease, Sangamo has an active pre-clinical program addressing Hemophilia (also part of the Shire collaboration). In addition, it has a number of non-partnered monogenic diseases under investigation. While it seems odd to recommend a stock based on pre-clinical data Sangamo is, in a certain extent, unique. It has a platform that, if it works as expected, can bring disease modifying compounds to numerous currently untreatable diseases. As such, data like the pre-clinical Huntington’s disease is additionally de-risking of not just that compound, but the platform. I expect the company to provide additional data on the monogenic disease programs over the next couple of years, which will slowly but surely de-risk these compounds and lead to a positive revaluation of the company. Of course, the major upcoming catalyst for Sangamo is the phase II data in 2013 on its HIV “functional cure.” We should be getting an update on the timing of that data in the coming months if not at the company’s analyst day early in December.