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Northwestern Researcher Looks to RNAi as a Way To Alleviate Symptoms of Parkinson s Disease

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Parkinson’s disease has proven to be a popular target for potential RNAi therapies. For instance, Alnylam Pharmaceuticals is experimenting with an siRNA-based treatment for the disease and CytRx has expressed a desire to pursue the indication.

But the interest in Parkinson’s disease is by no means limited to industry. Tatiana Tkatch, a researcher in the department of physiology at Northwestern University, has recently begun to use RNAi in a project — funded by a National Institute of Neurological Disorders and Stroke grant — using RNAi that she hopes will help alleviate the symptoms associated with the neurological condition.

The slowed movements and tremors experienced by Parkinson’s disease sufferers are believed to be caused by abnormalities in rhythmic activity in the globus pallidus, or GP, and subthalmic nucleus, or STN. High-frequency neuronal burst discharges in these parts of the brain are dependent on the expression of a combination of voltage-dependent Kv3 K+ channel subunits, according to Tkatch.

Tkatch aims in the RNAi project to determine whether suppression of Kv3.4 subunit expression in the GP and STN will be able to reduce the pathological, high-frequency neuronal burst discharges associated with Parkinson’s disease, she wrote in the grant’s abstract.

In a recent paper in Nature Neuroscience, Tkatch and colleagues reported that K+ channels with Kv3.1 or Kv3.2 subunits play a role in giving certain neurons the ability to discharge at high rates. These fast-spiking (FS) neurons “are critical participants in central nervous and sensory circuits,” they wrote in the paper’s abstract.

Evidence suggests that “a splice variant of Kv3.4 subunit coassembles with Kv3.1 subunits … in FS neurons … [enhancing] the spike repolarizing efficiency of the channels, thereby reducing spike duration and enabling higher repetitive spike rates,” they added. “These results suggest that manipulation of Kv3.4 subunit expression could be a useful means of controlling the dynamic range of FS neurons.”

While she has never worked with RNAi before, Tkatch told RNAi News that the decision to use the gene-silencing technology was an obvious one. “Of course, what is the best way to suppress RNA expression? It’s RNA interference,” she said. “It’s much easier than antisense [and] it’s much more productive, because you have to [use] a lot of antisense RNA to get suppression.”

With RNAi, she added, you can use “a thousand times less [and] have the same effect.

Tkatch said that she had designed a handful of siRNAs targeting Kv3.4, which were synthesized by Dharmacon, and has found one that gave sufficient knockdown of the K+ channel subunit.

“Some of them didn’t work, and several of them gave me 50 percent reduction,” she said. “Finally I got 85 percent reduction … [which I] checked in cell lines.”

Tkatch said that she is currently working on putting the siRNA together with a lentivirus vector for additional testing in vitro. After this, she intends on delivering the vectors into normal rats as a sort of safety study.

The vectors will be delivered directly into the brain, she noted. This work is expected to begin in the autumn.

“The goal of the grant is to get [siRNAs] into [a healthy] animal … to see how the behavior of cells might change,” she said. “You have to be sure that [the treatment] won’t change something else [in the brain] because what you want to do is change the diseased cells behavior, not to disrupt everything.”

In the grant’s abstract, Tkatch noted that she expects Kv3.4 will be an “excellent target for gene therapy approaches since its expression is highly specific for fast-spiking neurons, and the firing of non-targeted neurons in … areas [surrounding the GP and STN] should not be affected.”

The NINDS grant project runs between April 1, 2004 and Jan. 31, 2006, and is worth up to $230,000.

— DM


This month, Amy Pasquinelli, a researcher at the University of California, San Diego, was awarded a five-year grant worth up to $1.3 million in total costs to investigate the expression and function of the miroRNA let-7, which plays a role in developmental timing, in Caenorhabditis elegans.

The grant project aims to firstly characterize the sequence of let-7 RNA transcripts that give rise to the 22-nucleotide-long RNAs. Specifically, the sequence of the let-7 RNA primary transcript and processing intermediates will be determined, Pasquinelli wrote in the grant’s abstract. The let-7 RNA sequence elements that regulate processing will be defined by coupling in vitro assays to in vivo functional analyses.

The project will also identify genes involved in the expression of let-7 RNA. Pasquinelli wrote that mutations isolated in a forward genetic screen aimed at identifying genes that function with c/cr-1, the RNase that processes the roughly 70-nucleotide-long pre-let-7 RNA to the 22-nucleotide-long form, will be characterized and identified. Additionally, candidate genes containing ribonuclease, RNA helicase, or RNA binding domains will be tested for roles in let-7 RNA maturation by performing processing reactions in extracts where specific genes have been inactivated by RNAi.

According to Pasquinelli, the effort will finally look to determine the factors that mediate let-7-dependent regulation of specific targets.

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