Neurodegeneration treatments identified in study
compounds, which when combined, show the potential to treat
Huntingdon's and other neurodegenerative diseases.
Combinatorial drug therapies treat complex diseases in which a single drug given at an effective dose may provide relief, but only treats one component of the disease. These regimens are attractive because lower doses can be used to avoid side effects caused by high-drug concentrations that might be used if a single drug was used.
In addition, combinations of drugs that each provides relief from symptoms might provide greater relief when in combination. Combinatorial drug therapies are currently being used in treatments for certain cancers, AIDS and complex human diseases.
Researchers from the University of California have found that combinatorial drug therapies developed from these compounds halted the brain-cell damage caused by the fatal neurodegenerative disorders. Such types of therapies have proven effective in the treatment of other complex human diseases, like cancers and AIDS.
While human benefits from this study are years off, the research provides the first evidence that a regimen of complementary drugs can treat Huntington's.
The latest research involved performing tests on fruit flies. Researchers found combinatorial drug therapies developed from these compounds halted the brain-cell damage caused by the fatal, progressive neurodegenerative disorder. Such types of therapies have proven very effective in the treatment of other complex human diseases, like cancers and AIDS. And while any human benefits from this study are years off, the research provides the first evidence that a regimen of complementary drugs can treat Huntington's.
"Preclinical testing strategies such as those we used with fruit flies can result in a great savings of cost and time in developing potential disease treatments," said co-lead researcher Larry Marsh.
"They can serve to rapidly identify treatment regimens that are very likely to provide effective therapeutic benefit to patients."
Since Huntington's is a dominant disease, a child with one parent who carries the gene that creates these mutated proteins runs a 50 per cent chance of getting Huntington's disease. The disorder is progressive, and, while typically a late-onset disease, symptoms can appear in childhood. It causes uncontrolled movements, loss of intellectual capacity and emotional disturbances. It eventually results in death.
Huntington's disease is caused by an expansion of a repeated stretch of the amino acid glutamine within the Huntingdon protein (Htt). At least eight other neurodegenerative disorders are also caused by this polyglutamine activity. The pathology of these diseases is complex and involves multiple cellular events.
To address these complexities, the researchers matched compounds that together showed greater efficacy and at levels in which their toxicity is lessened.
Compounds were selected that individually have been shown in other fruit-fly tests and in mouse models to suppress neurodegeneration, but each targets different cellular processes. Included in these combinations are HDAC inhibitors, which also are showing great promise in cancer-treatment clinical trials. When combined, these compounds showed increased suppression qualities with no toxic side effects.
In one test, the researchers combined Congo red (a dye that blocks the formation of toxic polyglutamine fibrils), cystamine (an amino acid found to improve motor-neuron function in Huntington's-engineered mice) and SAHA (a synthetic HDAC inhibitor).
In the other test, they combined SAHA with Y-27632 (a protein that blocks polyglutamine aggregation) and geldanamycin (a naturally occurring compound found to relieve Parkinson's-like pathology).
"That's what's important to note," Marsh said. "Every drug is also a potential poison. Thus, we sought to find several drugs, each of which impacts a different point in the disease process, so that we could use low doses of each single drug, but together their combined effects all converge on a single disease process. This minimises toxic side effects while maximizing benefit."
The results of the study appear this week in the early online edition of the Proceedings of the National Academy of Sciences.
