In the previous article (Neuroinflamation Part 1) we reviewed evidence reported by Bjorquist and colleagues for neuroinflammation in Huntington's, where the authors found elevated cytokine levels which increased with disease stage. We also reported on other studies and observations showing that inflammation --and correlating cytokine levels -- form a major component of progression in neurodegenerative diseases.
Building on this work, scientists in academia, CHDI, and other pharmaceutical companies are hard at work on drugs that target inflammation, and several candidate molecules have progressed to testing in mouse models. However, most of these candidate drugs -- whose safety is unknown -- target downstream mechanisms in the inflammatory process, or those that occur after cytokine release. Trehalose -- whose safety is well known -- works in a very early part of the process by inhibiting cytokine release. Might it be time to reconsider this agent for therapeutic development?
Because trehalose is known to work very early in the inflammation process: inhibiting cytokine release. This disaccharide sugar functions in nature to protect cells from a wide range of environmental stressors, and is accepted as a safe food ingredient. It has also been shown to be neuroprotective in cell and animal models of Huntington's disease by stabilizing mutant huntingtin protein structure [Tanaka M 2004], and by increasing the destruction of mutant huntingtin [Sarkar S 2007]. And remarkably these benefits that were confirmed in several labs -- occurred with oral dosing -- which means only tiny doses of trehalose reached the bloodstream.
It is a good time for therapeutic development of trehalose.
What might a larger dose accomplish? A recent study in rats shows that larger doses of trehalose can greatly decrease cytokine levels -- the same ones found to be elevated in Huntingtons -- limit tissue damage, and preserve life after what would otherwise have been a fatal inflammatory stimulus [Perry VH 2004]. To achieve a larger blood stream dose, scientists gave trehalose into the abdominal cavity (IP injection). In more recent study done in cell models, scientists have shown that trehalose significantly decreases oxidative injury after an inflammatory stimulus [Béranger F 2008].
Why no trehalose drug development for Huntington's?
There are many reasons:
- It is considered a food or supplement. There would be minimal (if any) financial gain for a drug company unless a unique formulation (perhaps in solution) could be patented.
- It has had no pharmaceutical or academic champion in the U.S. Though creatine and CoQ-10 are supplements, both of these products were brought forward to clinical trials by powerful academic champions.
And there are technical barriers:
- It is very hard to measure levels of trehalose because it is quickly broken down into glucose. Being unable to measure levels prevents the ability to choose dosages, or even to assess its presence in vital tissues which is essential to drug development.
- It is impossible to achieve more than tiny blood stream levels when trehalose is given orally. Higher doses cause GI distress and diarrhea.
But -- by taking advantage of new knowledge about inflammation in Huntington's, there may be potential solutions to these technical problems.
- Though direct measure of trehalose is technically very difficult, cytokine levels in blood and/or cerebrospinal fluid could be an indirect measure of trehalose action. Further, measuring cytokine levels before and after systemic administration of trehalose could provide early proof of concept in people; that there is a measurable response in the targeted system. Cytokine response could also be used to guide dosage and dosage intervals.
- And though systemic administration of trehalose is more invasive than an oral route, IP or intravenous administration of trehalose would be as safe as administering a glucose solution. If trehalose is found to be beneficial, it could be given in this manner while scientists work to develop an oral formulation.
- Due to the great safety of trehalose, and the ability to follow cytokine response, it could also be given to presymptomatic individuals very early in the disease with very little risk.
Sitting on the shelf: My opinion: It is time to get trehalose off the shelf and into therapeutic development.
Tanaka M, Machida Y, Niu S, Ikeda T, Jana NR, Doi H, Kurosawa M, Nekooki M, Nukina N. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nat Med. 2004 Feb;10(2):148-54. Epub 2004 Jan 18. PubMed abstract
Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol Chem. 2007 Feb 23;282(8):5641-52. Epub 2006 Dec 20. PubMed abstract
Perry VH. The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease. Brain Behav Immun. 2004 Sep;18(5):407-13. PubMed abstract
Béranger F, Crozet C, Goldsborough A, Lehmann S. Trehalose impairs aggregation of PrPSc molecules and protects prion-infected cells against oxidative damage. Biochem Biophys Res Commun. 2008 Sep 12;374(1):44-8. doi: 10.1016/j.bbrc.2008.06.094. Epub 2008 Jul 3. PubMed abstract