CHDI and Isis to collaborate

HD Lighthouse Contributing Editor's Comment: The Lighthouse has been covering research into ways of silencing the HD gene. Our recent updates have dealt with RNA interference (RNAi). CHDI and Isis Pharmaceuticals are collaborating to develop an antisense drug.

Antisense is a different way to silence genes than RNAi. Messenger RNA is a single strand molecule (unlike the double stranded DNA). But like DNA, it can form double strands. The idea behind antisense is to introduce another strand that will bind to the RNA molecule. Once the antisense molecule is bound to the mRNA, an enzyme called RNase H binds to the double stranded region of the mRNA and catalyzes degradation of the mRNA. Without the mRNA protein cannot be synthesized.

RNA interference is the result of a serendipitous discovery in plant science. A botanist was trying to make more intensely purple petunias and added another gene for the color purple. The result was white or variegated petunias! Both purple genes were silenced. The reason for this is because of cellular defense mechanisms against the new RNA. The cell reacts as if the second RNA is from a virus and launches an attack that silences both the new RNA and the original RNA.

RNAi is more efficient at shutting down a gene than antisense technology. However, antisense technology may offer some advantages to the HD patient community. It may be that the very lack of efficiency is what is needed. In other words, it could be that lowering levels of both mutant and normal huntingtin's protein without knocking them down altogether will work as a treatment.

With RNAi, we face the problem that the normal huntingtin's protein is almost certainly needed so that efficiently shutting down both the mutant and normal protein isn't the way to go. RNAi clearly needs more work so that only the HD protein will be recognized and silenced, leaving a normal huntingtin's gene to function and that effort is likely to take years. In addition, the technique will have to be adapted to individual patients based on the way that their HD alleles differ from the normal huntingtin's protein alleles.

I spoke with Dr. Pacifici, CHDI's Chief Scientific Officer, about this exciting collaboration and he confirmed that targeting the upper and lower range of antisense effects is part of the appeal for this approach. Research from within the HD community on mice suggests that knocking down the HD protein about 40 percent is predicted to be beneficial; while the normal huntingtin's protein can be knocked down to levels as low as 25 percent without doing harm. Early data from the collaboration suggests that huntingtin levels can be knocked down substantially in mice for 6 weeks without any significant toxicity.

There's a possibility of doing some creative things with the dosing schedule to maximize effectiveness. One possibility is the 'picket fence' technique. This would be where the normal and HD proteins are shut down while the cells recover from the damage done by the HD protein but before the reduction in normal protein becomes harmful. Then both are allowed to be produced again for a period of time and then both are shut down again.

Dr. Pacifici commented on the antisense approach vs. the RNAi approach. “While we applaud the efforts of Neil Aronin and others working with RNAi to achieve HD allele specificity, that’s a next stage development in personalized medicine. In the meantime, there is evidence that the non-allele specific antisense approach will be safe and efficacious. There is a trajectory where we could get to clinical trials of this approach within the near future and it’s prudent to move ahead.”

There are other reasons for CHDI's investment in antisense technology in addition to the potentially quicker time towards treatments. Antisense is also appealing because unlike with most drugs, there are less issues with target validation and specificity.

Normally, in drug development, the researchers need to be sure that they have the right target to alleviate the disease. They also try to ensure that the drug interacts with just that target and not others. That is very hard to do and that is why virtually every drug has some side effects. Sometimes targets cannot be addressed with drugs at all because there isn't a way to affect the disease-causing protein without affecting other closely related and necessary proteins. However, in Huntington's Disease, the HD protein is clearly the target and the nature of antisense is that it is specific to the target because of its genetic sequence. Isis chooses regions of the gene that have very little cross-reactivity to the entire genome, resulting in a lower potential for toxicity.

The ideal drug for a neurological condition is one that can cross the blood brain barrier. However, there are a number of promising potential treatments such as an antisense drug which cannot do so. Dr. Pacifici explained that CHDI's goal for delivery of an antisense drug is to find the "least invasive and most convenient method balanced with the need to be sure that the drug will get to where it needs to be."

Getting treatments to the brain that won't cross the blood barrier is of necessity intrusive, but "The good news," says Dr. Pacifici "is that there are some pretty remarkable advances in the ability to do this."

CHDI and Isis will be comparing three different modes of delivery in animal studies. A pump mechanism and cannula (tube) will be implanted in one of three areas: at the base of the spine, in the ventricles of the brain and into the brain tissue. The antisense drug is highly soluble and long lasting (6-8 weeks).

-- Marsha L. Miller, Ph.D.
Posted to the HDL: 11-06-2007

Isis to Receive Up to $9.9 Million in Funding to Discover and Develop an Antisense Drug for Huntington's Disease

CARLSBAD, Calif., Oct 26, 2007 Isis Pharmaceuticals, Inc. (Nasdaq: ISIS) announced today that CHDI, Inc. (CHDI), a non-profit foundation pursuing treatments for Huntington's Disease (HD), will provide up to $9.9 million in funding to Isis for the discovery and development of an antisense drug for the treatment of HD, a fatal neurodegenerative disease. CHDI's funding builds upon an earlier successful collaboration between Isis and CHDI, in which CHDI provided Isis with funding for studies that demonstrated the feasibility of using antisense drugs to treat HD.

CHDI will provide Isis with up to $9.9 million in funding over three years to identify and conduct IND-enabling studies on an antisense drug targeting the huntingtin gene. Mutations in the huntingtin gene are responsible for the production of the abnormal Huntingtin protein, which ultimately leads to onset and progression of the neurodegenerative disease. Upon completion of IND-enabling studies, Isis and CHDI will continue to collaborate to ensure that any resulting drugs will be broadly available to HD patients and Isis has the right to continue clinical development of those drugs arising from the collaboration.

"We are pleased to expand our relationship with CHDI to identify a potential new therapy for Huntington's Disease, a condition for which there are limited treatment options available. Through several collaborative efforts, we have been focusing on the use of antisense drugs to inhibit production of central nervous system targets including Huntingtin. With ISIS 333611, our drug targeting SOD1 for a hereditary form of ALS, we have demonstrated in rodents that direct delivery of an antisense drug to the spinal fluid via an implantable pump effectively reduces SOD1 RNA and protein. This partnership with CHDI complements our work in ALS, and should enable us to create additional antisense drugs for central nervous system targets," said C. Frank Bennett, Ph.D., Senior Vice President of Research at Isis Pharmaceuticals, Inc.

Under the previous research contract with CHDI, Isis scientists demonstrated a reduction in Huntingtin protein expression in both brain and peripheral tissues of normal mice using Isis' proprietary second-generation antisense oligonucleotides. In addition, the inhibition of normal Huntingtin expression was well tolerated. These positive results by Isis have led to this expansion of the collaborative efforts between Isis and CHDI to identify a drug development candidate for the treatment of HD.

About Huntington's Disease

HD is a familial disease, passed from parent to child through a mutation in huntingtin gene that leads to the production of a variant of the Huntingtin protein. Inhibiting production of the Huntingtin protein is predicted to provide a therapeutic benefit in the treatment and/or prevention of HD. Each child of a HD parent has a 50-50 chance of inheriting the disease-inducing form of the huntingin gene, which causes programmed degeneration of brain cells and results in emotional disturbance, loss of intellectual faculties and uncontrolled movements. Most people with HD develop the symptoms at midlife but in some people onset occurs in infancy or old age. The average survival time after onset is approximately fifteen to twenty years. It is estimated that about one in every 10,000 persons has the disease-inducing form of the huntingin gene. At this time, there is no way to stop or reverse the course of HD.

About Isis Pharmaceuticals, Inc.

Isis is exploiting its expertise in RNA to discover and develop novel drugs for its product pipeline and for its partners. The Company has successfully commercialized the world's first antisense drug and has 18 drugs in development. Isis' drug development programs are focused on treating cardiovascular and metabolic diseases. Isis' partners are developing drugs for a wide variety of diseases. Ibis Biosciences, Inc., Isis' wholly owned subsidiary, is developing and commercializing the Ibis T5000(TM) Biosensor System, a revolutionary system to identify infectious organisms. As an innovator in RNA-based drug discovery and development, Isis is the owner or exclusive licensee of over 1,500 issued patents worldwide, and Isis is a joint owner of Regulus Therapeutics, LLC, a company focused on the discovery, development and commercialization of microRNA therapeutics. Additional information about Isis is available at http://www.isispharm.com.

In this press release, unless the context requires otherwise, "Isis," "Company," "we," "our," and "us" refers to Isis Pharmaceuticals and its subsidiaries.

Isis Pharmaceuticals, Ibis Biosciences and Ibis T5000 are registered trademarks or trademarks of Isis Pharmaceuticals, Inc.

Source: Isis Pharmaceuticals, Inc. press release