CAG number in brain increases over time which may cause HD to go faster, even before symptoms.
Creatine may slow this process.
The Research Goal: In 2003, another set of scientists had shown that CAG repeat number is not stable in brain cells over the lifespan of a person with Huntington's, and that this number increases prior to onset of symptoms [Kennedy L 2003]. This means that although the CAG number is stable in a blood test, it isn't stable in brain cells. The goal of Dr. McMurray's research was to study cell mechanisms related to increase in CAG number.
The Method: Among many other experiments, the authors studied the differences in brain cells in young HD mice, old HD mice, and normal mice. They subsequently studied HD mice that were engineered to lack the OGG1, (an enzyme that repairs DNA molecules) and compared results to HD mice who had normal OGG1.
The Results: The authors first showed that increases in brain CAG count occurred before or at onset of first symptoms in the HD mouse. They also showed that this coincided with increasing levels of a chemical called 7,8 hydro-8-oxoguanine (or by another name 8-oxy-G), which is a measure of OGG1 activity. Importantly, the authors went on to show that OGG1 is the cause: showing that the majority of HD mice lacking OGG1 had no increase in CAG repeat.
The Results We Don't have: Though in their discussion the authors argue that OGG1 activity is related to disease onset and progression, they don't report whether the Huntington's mouse with no OGG1 had any improvement.
Why is this Research Important? Making the assumption that OGG1 activity is important to disease progression, this research tells us that it is vitally important to keep OGG1 activity at a low level so that the added major toxicity of CAG expansion is not triggered. It may be that a stable CAG count causes the disease to smolder, and that it is CAG expansion that fans an ever-increasing fire. If this is the case, decreasing OGG1 activity before onset, or early in the disease is important.
Questions and Comments: Must we wait for a drug to be discovered that can directly decrease OGG1? The answer is probably no because we may already have a supplement/drug that will work. Researchers have published work showing that creatine decreases the product (or marker) for OGG1 activity (8-oxy-G or by another name 8OH2'dgG) in Huntington's patients when given at a dose of 8 grams per day [Hersch SM 2006]. These same researchers have shown that creatine given at higher doses of 20 or 30 grams per day brings this biomarker back to normal (page 31 presentation Institure of Medicine Forum on Biomarkers) and is associated with less brain atrophy. This same biomarker will be used in Huntington Study Group trials for creatine and co-enzyme Q-10. McMurray's work suggests that larger doses that bring the biomarker back to normal may be important.
Should we wait for more clinical trials? Phase II creatine dosing trials have taken in excess of 3 years. The Huntington Study Group/Avicena phase III clinical trial is not expected to begin before 2008. For some with HD or at risk for it, waiting for another 3-4 years for completion of phase III is a risk they won't want to take.
Words of Caution: If it is your decision to take high dose creatine (which is on my "favorites" list), it is essential that you treat this like the real medicine it is: consult with your own doctor and obtain a quality supplement. High dose creatine has side effects, and creatine products containing impurities may make oxidative injury worse. My advice; partner with your doctor or don't take high doses.
Kennedy L, Evans E, Chen CM, Craven L, Detloff PJ, Ennis M, Shelbourne PF. Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. Hum Mol Genet. 2003 Dec 15;12(24):3359-67. Epub 2003 Oct 21. PubMed abstract
Hersch SM, Gevorkian S, Marder K, Moskowitz C, Feigin A, Cox M, Como P, Zimmerman C, Lin M, Zhang L, Ulug AM, Beal MF, Matson W, Bogdanov M, Ebbel E, Zaleta A, Kaneko Y, Jenkins B, Hevelone N, Zhang H, Yu H, Schoenfeld D, Ferrante R, Rosas HD. Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2'dG. Neurology. 2006 Jan 24;66(2):250-2. PubMed abstract