PropThink: Early Hope for Huntington's Disease and Further Validation of Sangamo Platform
(Thomson Reuters ONE) -
By David Sobek
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. You can see the
rest of this article by clicking here.
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Datum: 19.10.2012 - 14:31 Uhr
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