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Isis Pharmaceuticals, Genzyme, Expression Genetics, Alnylam Pharmaceuticals, Qiagen, University of Massachusetts

Isis, Genzyme Begin Phase III Trial of Antisense-Based Cholesterol Drug
Isis Pharmaceuticals announced this week that it has begun a new phase III trial of its antisense-based hypercholesterolemia drug mipomersen in patients with heterozygous familial hypercholesterolemia.
The trial is being conducted with partner Genzyme, which exclusively licensed the drug’s rights earlier this year.
The phase III trial will evaluate the safety and efficacy of mipomersen, which targets apolipoprotein B, in about 100 patients who have heFH and coronary artery disease, according to Isis. The primary endpoint will be percent reduction in LDL cholesterol, and data are expected to be available in 2010.
Isis said that it will initially seek approval for mipomersen as a treatment for high cholesterol in patients with homozygous FH. An ongoing phase III study in that population is expected to be completed by the end of the year. Isis expects to submit the drug to US regulators in the second half of 2010.

Alnylam’s Q2 Revenues, R&D Costs Jump
Alnylam Pharmaceuticals this week posted sharply increased second-quarter revenues, although the company’s net loss rose slightly, in part due to higher research and development spending.
For the quarter, Alnylam’s second-quarter revenues shot up to $23.8 million from $9.1 million in the same period a year earlier. The company attributed the increase mostly to $13.4 million in collaboration revenue from Roche (see RNAi News, 7/12/2007).
The firm’s second-quarter net loss edged up to $12.8 million, or $0.31 per share, from $12.7 million, or $0.34 per share.
Alnylam’s R&D costs in the quarter jumped to $29.6 million from $18.8 million as a result of license fees paid to, among others, Isis Pharmaceuticals, as well as a $2.1 million related to the premium paid for shares of Tekmira Pharmaceuticals (see RNAi News, 4/3/2008).
The company’s overall operating costs, meanwhile, rose to $36.7 million from $24.1 million in the second quarter last year.
As of June 30, Alnylam had cash, cash equivalents, and marketable securities totaling $538.3 million.
Looking ahead, the company said that it expects its cash, cash equivalents, and marketable securities balance will be about $500 million by the end of 2008.

Expression Genetics Closes $12M Financing Round
Expression Genetics said this week that it has closed a $12 million Series B round of financing.
According to the company, a portion of the round’s proceeds will be used to continue development of siRNA delivery technologies, including the TheraSilence platform.
"This [financing] will allow us to expedite the overall clinical program for [the non-RNAi ovarian cancer drug] EGEN-001 and enable us to continue development of the promising technologies for delivery of therapeutic RNAi,” Danny Lewis, CEO of Expression Genetics, said in a statement.

Alnylam Licenses Core RNAa Intellectual Property
Alnylam Pharmaceuticals this week said that it has exclusively licensed certain intellectual property related to a gene up-regulation technology termed RNA activation, or RNAa.
The licenses were struck with the University of Texas Southwestern Medical Center, the University of California, San Francisco, and the Salk Institute for Biological Studies.
"Alnylam is committed to scientific and IP leadership across all areas of modern biology's RNA revolution, including our ongoing efforts in RNAi and microRNA therapeutics, and now RNAa," Alnylam CEO John Maraganore said in a statement.
"While there's more to understand in this emerging biology, RNAa defines a new application for double-stranded RNAs that could have the potential to create an entirely new therapeutic platform for Alnylam,” he added. “Many human diseases are caused by the abnormally low expression of proteins, and RNAa could be used to treat these disorders through selective transcriptional gene activation.”

Qiagen Second-Quarter Revenues up 61 Percent
Qiagen reported this week that its second-quarter revenues rose 61 percent and its adjusted net income, which excludes acquisition-related items, increased 57 percent year over year.
For the three-month period ended June 30, the firm generated revenues of $217.9 million compared to $135 million for the second quarter of 2007.
Qiagen’s profit for the quarter was $23.2 million, or $0.11 per share, compared to a profit of $22.6 million, or $0.14 per share, for the comparable period a year ago. The results include charges of $24.1 million in the second quarter related to acquisition and integration costs and amortization of acquired intellectual property compared with $4 million for similar charges the year before. On an adjusted basis, Qiagen’s net income for the most recent quarter was $40.4 million, up from adjusted net income of $25.8 million the year before.
Qiagen’s R&D spending nearly doubled in the quarter to $23.8 million from $12.7 million, while its SG&A expenses increased 70.9 percent to $77.9 million from $45.6 million.
The company finished the quarter with $380.7 million in cash and cash equivalents.
Qiagen said that it expects its full-year 2008 revenues to be in the range of between $889 million and $919 million.

MicroRNA Found to Mediate Brain’s Alcohol Tolerance
A brain-specific microRNA has a key role in the development of some forms of alcohol tolerance, new research suggests.
In a paper appearing online last week in Neuron, researchers from the University of Massachusetts identified a miRNA — called miR-9 — that is up-regulated in rat brain cells in the presence of alcohol. The miRNA seems to exert post-transcriptional control over the stability of certain alcohol tolerance-related splice variants. That, in turn, can alter the way neurons react to alcohol, boosting their tolerance.
“This represents a novel and elegant mechanism by which neurons are able to adapt to alcohol,” senior author Steven Treistman, a neurobiologist and director of the University of Massachusetts’ Brudnick Neuropsychiatric Research Institute, said in a statement. “Moreover, since adaptation, or tolerance, to the drug likely contributes to alcohol abuse, our findings identify a potential molecular target for therapeutic intervention.”
Regular exposure to alcohol can decrease an individual’s alcohol sensitivity, increasing the likelihood that he or she will become dependent on the substance. Previous research has shown that such tolerance involves BK channels, large-conductance calcium and voltage-activated potassium channels that regulate neuronal excitability. Over time, the density of these channels decreases in regions of the brain called the supraoptic nucleus, or SON, and the striatum as alcohol tolerance increases.
In an effort to understand the molecular basis of this alcohol tolerance, Treistman and his colleagues looked at the BK mRNA variants present in the SON and striatum of rat brain cells that were unexposed or exposed to alcohol. They found several BK splice variants — the identity of which shifted in the presence of alcohol, apparently post-transcriptional mechanisms.
That observation fueled speculation that one or more miRNAs was involved. To determine which miRNAs, if any, regulate BK mRNA, the team looked for BK mRNA-interacting miRNAs by base-pairing more than 100 rodent neuronal miRNAs with the 3’ untranslated region of rat BK mRNA.
The search turned up miR-9, a brain-specific miRNA involved in neurogenesis. Subsequent experiments showed that miR-9 levels increase in response to alcohol, concurrent with alterations in BK mRNA community composition. This alcohol-dependent post-transcriptional BK mRNA regulation appears to cull the most alcohol-sensitive BK splice variants, leaving behind more tolerant variants. 
But miR-9’s influence did not seem to stop at the BK mRNA. The miRNA also seems to mediate at least ten other alcohol-related mRNA targets in the brain. These mRNAs, most of which are down-regulated by miR-9, appear to be involved in processes such as neuronal excitability, gene expression, lipid metabolism, and pre-synaptic function.
“Alcohol, via miR-9 upregulation, regulates additional targets, suggesting a central role for miR-9 in alcohol’s actions in the CNS,” the authors wrote.
Even so, miR-9 doesn’t explain all BK channel-related alcohol tolerance. Some BK channel tolerance is governed by miR-9, but there are also situations in which tolerance occurs in the absence of miR-9. Similarly, there are different forms of alcohol tolerance, ranging from acute to chronic, that may depend on the action of other miRNAs. Still, the work provides new insights into alcohol tolerance that may eventually benefit those with alcohol dependence.
“The study demonstrates for the first time that alcohol exposure can cause rapid changes in miRNA levels, altering gene expression and perhaps behavior,” Antonio Noronha, director of the National Institute of Alcohol Abuse and Alcoholism’s Division of Neuroscience and Behavior, said in a statement. “In future studies, it will be interesting to determine if similar miRNA-based regulatory mechanisms influence alcohol problems in human populations.”

The Scan

Study Links Genetic Risk for ADHD With Alzheimer's Disease

A higher polygenic risk score for attention-deficit/hyperactivity disorder is also linked to cognitive decline and Alzheimer's disease, a new study in Molecular Psychiatry finds.

Study Offers Insights Into Role of Structural Variants in Cancer

A new study in Nature using cell lines shows that structural variants can enable oncogene activation.

Computer Model Uses Genetics, Health Data to Predict Mental Disorders

A new model in JAMA Psychiatry finds combining genetic and health record data can predict a mental disorder diagnosis before one is made clinically.

Study Tracks Off-Target Gene Edits Linked to Epigenetic Features

Using machine learning, researchers characterize in BMC Genomics the potential off-target effects of 19 computed or experimentally determined epigenetic features during CRISPR-Cas9 editing.