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| Dr. Frank Bennett (HDSA-San Diego photo) |
Isis Pharmaceuticals, Inc. has made substantial progress in the search for a drug to stop Huntington’s disease at its root cause, according to Dr. Frank Bennett, the company’s senior vice president for research.
The Carlsbad, Calif. company, which began its Huntington’s disease treatment project in late 2007 with funding from the Los Angeles-based CHDI Foundation, Inc., has narrowed its choice of possible drugs to about a dozen from the several thousand candidate molecules that company scientists designed and manufactured using Isis’s highly specialized industrial process. These drug molecules were created with the aim of stopping the actions of the gene huntingtin in human brain cells. The company has been testing the dozen final candidates in human skin cells and lab animals and, according to Dr. Bennett, has achieved some encouraging results: the substances appear safe and are well distributed in the brains of the test animals.
Isis is a world leader in antisense technology, which employs moderately-sized molecules – each one representing a possible drug – to block messenger RNA from producing proteins. (Click here for an earlier report on Isis, HD, and antisense.)
Initial success with new technology
On May 20, 2009, Isis and its partner Genzyme Corp. announced successful test results in humans for Isis’s Mipomersen, an antisense drug for people who suffer from familial Hypercholesterolemia (extremely high cholesterol). The test was the so-called Phase III trial, the last in a series of trials before a drug can go to market. Mipomersen is the first antisense drug in history to be delivered systemically, that is, through the bloodstream.
Messenger RNA builds proteins using the genetic code from DNA. In the case of Huntington’s disease, an abnormally elongated huntingtin gene produces a faulty huntingtin protein that wreaks havoc with brain cells, leading to massive cell death and the devastating symptoms such as loss of the ability to walk, talk, think, and care for oneself. HD is ultimately fatal.
Isis’s molecules are known as oligonucleotides or, simply, oligos. In technical terms, they are referred to as synthetic nucleic acids. The correct oligo will be able to bind with the messenger RNA and stop it from making the harmful protein. As described by Dr. Bennett in 2008, this approach is like a “laser-guided missile” for attacking Huntington’s.
On track for treating HD
“We are still on track to identify a drug for the treatment of Huntington’s disease,” Dr. Bennett said in a June 15 interview at Isis. “Our goal is to identify a development candidate this year that will then enter into the pre-clinical work that you need to do to support going into humans.” He expects Isis to choose a final candidate by the end of 2009.
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| Isis scientist Irma Sotelo-New demonstrates use of a rotary vaporizer in the purification of molecules in the HD project (photo by HDSA-San Diego). |
Isis would then seek approval from the Food and Drug Administration (FDA) to run a Phase I trial in humans sometime in 2011.
Isis first tested its dozen or so candidate oligos in skin cells known as fibroblasts taken from people with HD, Dr. Bennett explained.
“We’re not looking for behavioral effects in the cell,” he stated. “We’re just looking at the cells as a source for the messenger RNA that codes for the CAG-expanded form of huntingtin.” CAG is the trinucleotide “word” within the huntingtin gene that is repeated too many times in the abnormal, disease-causing form of the gene. Most people have between 10-35 repeats of the CAG at a certain point within their huntingtin gene. CAG repeat numbers above 35 are not normal and can cause HD, and 40 or more repeats signify that a person will definitely develop HD.
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| Isis neuroscientist Curt Mazur examines a dissected monkey brain for effects of one of the oligos (photo by HDSA-San Diego). |
Animal tests successful
Isis next tested the oligos in mice, dogs, and monkeys to check for three things: potency (strength), toxicity (harmful side effects), and pharmacokinetics (distribution of the drug and how long its remains in the tissue). So far Isis researchers have found no serious side effects in the human cells or the animals.
Significantly, the oligos have reached all areas of the mouse brains, Dr. Bennett said. This means that Isis has avoided the all-important blood brain barrier – the brain’s self-protection mechanism against foreign substances. The brains were completely bathed with the oligo, thus giving this vital organ full protection. HD first affects the cerebral region known as the striatum but eventually attacks other areas, severely shrinking the brain by the time a patient dies.
Isis has been able to use the huntingtin oligos to “knock down” or reduce the huntingtin protein by up to 80 percent in the mouse brains, with no apparent serious side effects so far. The key is to use the correct amount of drug in order to halt bad huntingtin but avoid hampering the normal function of the protein, Dr. Bennett explained.
“Surprisingly good” news
“It’s been very encouraging that we’re not seeing a lot of adverse effects from inhibiting huntingtin,” he elaborated. “Obviously it’s a normal gene that’s in everybody, and there were concerns that if you inhibited it, it wouldn’t be tolerated. But we’ve been able to inhibit 80 percent or better and have really not seen any adverse events that we can attribute to inhibiting huntingtin. That’s surprisingly good.”
HD patients have a normal huntingtin gene from the non-affected parent and a defective gene from the affected parent. The absence of serious effects from knocking down normal huntingtin means that Isis’s oligo has a good chance of being a safe drug in humans.
Scientists have only begun to understand the regular functions of the huntingtin gene and its proteins. The Isis research could provide important new data in this area of HD inquiry.
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| Dr. Alejandro Lloret observes mouse tissue containing an Isis oligo (photo by HDSA-San Diego). |
Isis is measuring the absorption and tolerance of the oligos in mouse spleens, kidneys, livers, and brains. Scientists dissect the striata of mice and monkeys to search for physical evidence of the oligos’ effects. “This will give us an idea of the pathways that the normal and the mutant huntingtin take,” said Dr. Alejandro Lloret, an Isis specialist in neurodegenerative diseases and biomedical sciences. (Click here to read more about Dr. Lloret.) Data suggest that the defective huntingtin gene may be causing the huntingtin protein to function differently, Lloret added.
HD mice observed
Isis has also injected its oligos into transgenic mice that have a copy of the abnormal human huntingtin gene and therefore develop traits of the disease. The behavior of injected mice – and the potential effect of the oligos – is being observed in the laboratories of Dr. Don Cleveland, a professor of medicine at the University of California, San Diego, and Dr. Marie-Francoise Chesselet, a physician and neurobiologist at the University of California, Los Angeles.
Drs. Cleveland and Chesselet will then dissect the mice to check for the level of huntingtin knock-down and other evidence of what happens to brain cells, explained Dr. Douglas Macdonald, a pharmacologist and CHDI’s director of drug discovery, in an interview on June 17.
Another benefit of the Isis-CHDI project is the knowledge gained by testing the candidate oligos in the mice, Dr. Macdonald added. For instance, even though those specific oligos may not be the final clinical candidate, the many experiments being done may help scientists understand the disease process more broadly.
Going after the defective gene
A big key to the ultimate impact of the Isis oligo will be to allow the normal huntingtin gene to do its work while blocking the bad one. Right now the oligos knock down both.
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| Dr. Doug Macdonald |
“We would love to lower only the mutant, because that’s what’s causing the disease,” Dr. Macdonald said. “That’s really difficult to do, but several investigators are working on such an approach and we will be ready to translate those discoveries into a possible second-generation oligo drug.”
Lloret added that with “a little imagination,” Isis may have a chance of targeting only the bad huntingtin.
While Isis and CHDI are confident of finding the right oligo for a first-generation drug, they must still find a safe and effective way of delivering it into the human body. Isis currently plans to inject the oligo directly into the ventricles of the brain, thus putting the drug into immediate contact with the tissues needing treatment. Another, probably less desirable possibility is to inject the substance into fluid around the spinal cord and let it migrate into the brain.
Planning for human trials
Dr. Bennett stated that after testing mice, Isis will put the oligos into monkeys again later this year and in 2010 to test for efficacy and toxicity. If the 2009 tests go well, Isis will file an “investigational new drug” application with the FDA in preparation for the Phase I human trial in 2011. Isis and CHDI are starting to contact doctors with clinical experience to begin mapping a Phase I strategy.
Dr. Bennett cautioned that, despite the progress towards a drug, much could still go wrong. And even if completely successful, the drug will require at least six or seven years of testing before it can go to market. Because antisense drugs are in their infancy, the FDA will be especially cautious with a new drug of this kind, he said.
“You want to make sure that you’re not hurting patients,” he explained. “I understand the frustration of the patient population with that. It is important that you do this right so that you have the chance of benefiting the broader patient population as a whole.
“If you look at the industry, once you start a clinical trial, there’s a ten percent chance that you’ll be successful. We’re in an industry where, if you want to make a safe bet, you bet against the drug. That’s just the nature of the business that we’re in. There are lot of reasons why drugs fail in clinical testing. I don’t want to give your audience the hope that we have a guaranteed drug. There’s still a tremendous amount of risk associated with this project, and so we’re working very hard and we’re trying to mitigate those risks.”
Optimism about a treatment
Isis is getting positive exposure for its Huntington’s disease research. The company presented its research at the closely watched CHDI meeting in Cannes, France, in April and plans to make additional presentations at the World Congress for Huntington’s Disease in Vancouver, British Columbia, in September and at the Society for Neuroscience annual meeting in Chicago in October.
“I’m optimistic that we’ll find a treatment,” Dr. Bennett said. “I don’t think we’ll cure the disease. But I think we’ll have a treatment that will have an impact on the rate of progression of the disease.” A successful drug could later be fine-tuned to prevent symptoms from ever appearing in people who have tested positive for the disease, he added.
“We have a team that’s working very hard on trying to develop a therapy,” Dr. Bennett said. “We are very pleased where we are. So keep your fingers crossed that it continues to progress forward.”
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