Friday, November 20, 2015

Huntington's hope

Gene silencing and editing techniques aimed at modifying the mutant huntingtin gene (HTT) to reduce levels of the protein promise to change the landscape for patients with Huntington's disease (HD), according to several reports presented at the Society for Neuroscience annual meeting here in October...

Scientists at the University of British Columbia's Centre for Molecular Medicine and Therapeutics (CMMT) identified eight of the most common genetic variations on the HTT gene associated with HD and tested specialized antisense oligonucleotides (ASOs) in blood cells from HD patients to assess whether the drugs can silence, or turn off, the mutated gene and reduce levels of the toxic huntingtin protein. The drugs work by binding to the messenger RNA and inducing degradation of the transcript, preventing synthesis of the mutant protein...

Dr. Hayden's team has evaluated ASOs that target one of the HD SNPs they identified, and they are now using a potent and well tolerated ASO in animals to see whether it is effective at reducing the mutant huntingtin protein. They are developing a panel of ASOs targeting HD SNPs specific to the three most common HD HTT haplotypes.

Lowering mutant huntingtin in animal models of HD has proven effective at reducing the motor and behavioral symptoms, as well as the neuropathology observed in the brain. RNA interference methods are also being developed by other groups to reduce the huntingtin protein...

The first clinical trial using a non-selective HTT silencing approach (targeting the wild-type and mutant genes) is now underway...

The drug, ISIS-HTTRx, is injected into the spinal fluid...

We designed ISIS-HTTRx to target the huntingtin gene and reduce the production of huntingtin protein,” said C. Frank Bennett, PhD, senior vice president of research at Isis Pharmaceuticals...

Scientists at the Institute for Regenerative Cures and the Genome Center at the University of California, Davis, are using transcription-like effectors (TALEs) in primary human HD fibroblasts and neurons to see if they can reduce mutant huntingtin. TALEs are DNA-binding molecules that can be designed to target single nucleotide polymorphisms in the mutant allele. The TALE molecules either cause a CAG collapse in the expanded mutant allele or provide transcriptional repression of the mutant gene...

The TALE recognizes sequences in DNA and makes a double-stranded cut, which would collapse the CAG length down to a non-disease stage, or, when using KRAB, cause transcriptional repression the mutant allele...

The research team conducted real-time quantitative assays to measure how much transcription of the mutated gene occurred. The technique lowered the expression of the mutant gene to near-normal levels. The expression of the healthy gene was not affected by the treatments...

Nicolas Merienne, PhD, and his colleagues in the laboratory of cellular and molecular neurotherapies at Lausanne University Hospital in Switzerland, used the gene editing technology, referred to as clustered regularly interspaced short palindromic repeats (CRISPR), to test its power to edit out the mutant gene and alter the reading frame of the HTT gene that would lead to a loss of mutant HTT expression...

“We've only done a local proof of principle in the striatum,” Dr. Merienne said. “We have not looked for behavioral changes or functional recovery yet.” He added that the researchers are now evaluating the impact of allele or non-allele-specific mutant HTT editing in human neurons cultured from HD patients.

“CRISPR is by far the most efficient system,” said Nicole D├ęglon, PhD, head of the laboratory at Lausanne University Hospital. “We are still trying to identify the efficient and safe system to use in humans. One of the major concerns is treating enough cells in the brain to have a therapeutic effect. We have to be absolutely sure that we are not doing anything else off of our target gene.”...

Christopher Ross, MD, PhD, a professor of psychiatry, neurology, pharmacology, and neuroscience at Johns Hopkins University School of Medicine and director of the Baltimore Huntington's Disease Center at Hopkins, said that the nature of HD — it is a triplet repeat expansion — is that it is hard to get an intervention to the mutated allele without affecting the wild-type allele.

“One strategy is to target other parts of the HD message whose sequence is specific to the mutant allele,” Dr. Ross said. “This strategy is attempting to correct the gene defect, and another difficulty is that you need to get every cell, or at least a significant number of them. Delivery of these therapeutic agents into relevant areas of the brain is very challenging. You use these technologies to edit the mutant gene, and thereby disrupt its ability to transcribe mRNA to make mutant protein...

Willeke van Roon-Mom, PhD, an assistant professor at Leiden University Medical Center in the Netherlands, also studies transcriptional changes in both cell models of HD and HD patients. She also studies possible therapeutic treatments, including small antibodies specific for the huntingtin protein and ASOs.

“These approaches make a lot of sense,” she said, commenting on the studies, noting that these approaches could reduce up to 50 percent of the mutant huntingtin protein. “Scientists can design a drug that only targets the sequence in which they are interested. I think this strategy will work. But you always have patients who don't have the common SNPs, so other strategies are needed too.”

http://journals.lww.com/neurotodayonline/Fulltext/2015/11190/News_from_the_Society_for_Neuroscience_Annual.6.aspx

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