Huntington's Disease Treatment - Treatments for Huntington's Disease

Over the years, I have found that going to Huntington's Disease conferences is a little like riding a roller coaster. I remember the tears of joy I shed when the Huntingtons Disease gene discovery was announced, and several years later my enthusiasm after hearing the first reports of benefit in mice induced by minocycline, Co-Q10, and creatine.

And now, on almost a daily basis there are reports of one or another treatment for Huntington's Disease that works in yeast, or flies, or mice. But at the end of the day, I would always come back to the ground level reality that nothing terribly good was in sight for the Huntington's Disease patients I care about.

This CHDI (Cure HD Initiative) conference was a little different. I think I see some light at the end of the tunnel. And though I can't know how far away a cure for Huntington's Disease is (and it's always longer than we hope), I believe effective treatments for Huntington's Disease are coming.

Source:
Dr. LaVonne Veatch Goodman on the Huntington's Disease Drug Works website on Huntington's Disease treatments.

Almost two years ago, CHDI (Cure Huntington's Disease Initiative) was added to the Huntington's Disease (HD) drug development team with the goal of helping to bring together the scientific "know how" of academic scientists and the experience of the pharmaceutical industry. CHDI is a Huntington's Disease drug company that has no laboratories of its own but expertly solicits and provides incentives to industry partners to work with scientists to meet the needs of the HD drug development process. The goal is to facilitate the most rapid development of drugs for Huntington's Disease.

As collaborative partners, CHDI has funded academic labs and pharmaceutical companies, providing more than ten million dollars each year for 11 academic labs, 10 biotech and pharmaceutical companies, and 20 vendors (product suppliers). Funded projects to search for treatments for Huntington's Disease include large scale screening for effective HD drug candidates and drug combinations.

There are others that modify and improve molecules selected from screens. These steps maximize potency, decrease toxicity, and improve brain delivery-- turning the molecule into the best drug for Huntington's Disease. Best molecules are then tested in the equivalent of a mouse model factory. Several companies are working on specialized types of drugs to treat Huntington's Disease. Still others are working on biomarkers that can speed the Huntington's Disease clinical trial process.

Source:
Dr. LaVonne Veatch Goodman on the Huntington's Disease Drug Works website on how to treat Huntington's Disease.

Drugs for HD: A Best Case Scenario
by LaVonne Veatch Goodman, M.D.

The Huntington's community has been without treatment for so long that we don't let ourselves even think about success. And true to that pattern, both Jim Tretheway and I recently gave cautious overviews on the status of CHDI and HD drug development. This week, I'll take different approach using a real world example that gives a best case scenario that could be possible for HD following the advances made in the past two years by scientists and CHDI. Why do this? We need to be prepared for best case too.

CML-Gleevec example Just a few years ago, chronic myeloid leukemia (CML) was a death sentence. Now with the drug Gleevec, many people with CML are free of the disease for years and may be cured. The Gleevec story demonstrates that drug development can go very fast when specific hurdles are passed.

CML is caused by a single gene mutation, not one that is inherited like HD, but one that occurs later in life due to gene damage. For CML the hurdles were finding the defective gene, finding the "switch" the gene turned on to cause the disease, and making a safe drug that turned off the switch.

CML Timeline It took more than 20 years and several teams of research scientists to find the gene and the molecular switch that caused leukemia. During some of these same years, scientists at Novartis, a large pharmaceutical company, were developing drugs (for another disease) that could work at this switch.

Then in 1993 they got together. After two years of drug development at Novartis, they found a drug that cured leukemia in a mouse model. Then delay. Novartis, who owned the drug, wasn't sure it wanted to proceed, because CML (like HD) is a rare disease, and the company wasn't convinced the drug would make money. Finally in late 1998, this drug, now called Gleevec entered clinical trials.

Huntington's Timeline Starting to sound familiar? It has taken more than 20 research years to find the Huntington's gene and to sort through the multitude of disease switches it turns on.

Then, in a very important breakthrough in 2006, Dr. Hayden and colleagues identified what may be the master switch that starts the disease process and cured the mouse by turning the switch off. This switch is a natural chemical in the body called caspase-6. And in the exciting follow up to that research, CHDI partnered with Amphora Discovery Corp, a drug company already working on drugs that can block this switch.

And in a time frame that could be similar to Gleevec, they predict it will take about a year to identify the best drug candidates to test in mice, and another year or two years to complete these tests. Clinical trials in people could start soon after that.

Gleevec Clinical Trials Novartis announced amazingly good first clinical trial results in 1999: all 31 CML patients had remission of their disease. The follow-on trials were quickly begun, with enrollment of more than one thousand CML people (at 3 stages of the disease) by the end of 2000.

In an equally amazing accomplishment, patient advocacy groups, their doctors, and Novartis created expanded access (compassionate care) programs for another 5000 patients, before FDA approval in 2001. And still amazing, Novartis had the drug ready to ship to pharmacies the day after FDA approval. That's right: it took just a little more than 2 years of clinical trials until every CML patient could use the drug.

Huntington's Analogy Not sounding as familiar now? Clinical trials are harder in HD than CML, because drug response is much harder to measure in HD. But a bigger problem is that we do not yet have a clinical trial system that is ready to move fast even when the perfect drug is found.

Why is the Gleevec analogy important? First it gives us perspective on how far we've come, and it should get us to thinking about what might be possible in the next few years. There is a real chance that we'll have a drug that cures the HD mouse in two or three years. The time is right to fix the HD clinical trial system so we can get drugs to people as quickly as Gleevec.

Source:
Dr. LaVonne Veatch Goodman, Huntington's Disease Drug Works website on treatments for Huntington's Disease.

Supplement Derived from Green Tea May Treat HD

Researchers from the Max Delbrueck Center in Germay report promising results for a nutritional supplement derived from green tea. Summary by Dr. LaVonne Veatch Goodman posted on www.HDDrugWorks.org, Huntington's Disease Drug Works.

The Goal - To test whether EGCG (-)-epigallocatechin-3-gallate, a nutritional supplement found in green tea, may be useful in treating Huntington's Disease. Scientists tested the effects of EGCG in laboratory models of HD, including yeast and fruit flies (but not mice or people). They go on to explain how this potential drug is thought to work at a very early part of the disease process.

The Method Researchers found EGCG by running thousands of natural compounds through a large scale testing procedure that checked each molecule's ability to stop aggregation or clumping of the mutant HD protein. Next they studied the effects of adding EGCG in increasing amounts to mutant HD protein in test tube experiments, then studied the molecule's effect in yeast and fruit fly models of Huntington's.

The Results EGCG decreased aggregation of mutant HD protein in test tube (in vitro) studies with benefit increasing with dose. Most importantly they showed that EGCG decreased formation of oligomers and fibrils, the toxic small fragments thought to start the domino effect disease cascade. The authors showed that EGCG changed the shape of these structures, which made them less toxic.

In further studies, the authors showed that EGCG significantly improved survival and decreased aggregate number by 40% in a yeast model of HD. Finally the authors showed that EGCG decreased toxicity in a fruit fly model of HD by 29% and significantly improved motor function.

Why is it Important? EGCG is a nutritional supplement that is available over-the-counter at modest expense and has a good safety record for long term use. Because experts believe that best drugs for HD will be those that target early disease events (Gusella and MacDonald 2006), EGCG should be an especially good drug candidate. It has potential both to delay disease onset, and to slow progression after symptoms develop.

Comments - Of course the obvious question is whether those with Huntington's (and those at risk) should take EGCG found in green tea. My comment after reading this and another recent review article (Mandel et al 2005) that catalogues EGCG's activity as free radical scavenger, iron chelator, modulator of pro-survival genes, and stimulator of protective membrane kinase enzymes, etc. is "Why not?"

If you choose to use EGCG, the next question is what dose. My educated guess is that dosages in the range of 600 to 900 mg/day of high quality supplement are reasonable. As always when choosing supplements, make sure the product you use has been tested for content and contaminants, preferably by Consumer Lab or U.S. Pharmacopeia. Based on Consumer Lab testing, I recommend 2 or 3 capsules of Life Extension's Mega Green Tea Extract. Each capsule contains 326 mg of EGCG and can be ordered online at a cost of 21 dollars per 100 capsules. Several other products tested were substandard, containing lower than advertised EGCG dosage and high levels of contaminants. I specifically don't recommend that you try to get an adequate dose of EGCG by drinking green tea, as this would require at least 10 cups a day with high content of caffeine and unknown quantities of EGCG and contaminants.

EGCG is yet another agent to add to the list of potentially helpful HD treatments. It adds to the same old dilemma that HD people know too well: do you wait long years until there is definitive proof that a treatment works or do you spend your money, time, and hope on agents that scientists have shown might work. It's not an easy choice.

The Report
Ehrnhoefer DE, Duennwald M, Markovic P, Wacker JL, Engemann S, Roark M, Legleiter J, Marsh JL, Thompson LM, Lindquist S, Muchowski PJ, Wanker EE. Green tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease models. Hum Mol Genet. 2006 Sep 15;15(18):2743-51. PubMed abstract

For References for this article, see www.HDDrugWorks.org