Promising treatments for Huntington's disease identified in UCI study

Main Category: Huntingtons Disease
Article Date: 15 Feb 2005 - 12:00 PDT

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UC Irvine researchers have identified several promising drug compounds that when combined show the potential to treat Huntington's disease.

In tests on fruit flies, Larry Marsh and Leslie Thompson found that 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. Study results appear this week in the early online edition of the Proceedings of the National Academy of Sciences.

"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," Marsh said. "They can serve to rapidly identify treatment regimens that are very likely to provide effective therapeutic benefit to patients."

In developing these drug combinations, Marsh and Thompson chose compounds 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.

"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 minimizes toxic side effects while maximizing benefit."

Since Huntington's is a dominant disease, a child with one parent who carries the gene that creates these mutated proteins runs a 50-percent 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. It has been described in medical literature under a host of different names since the Middle Ages.

In previous studies on Huntington's disease, Marsh and Thompson, together with Joan Steffan of UCI, found that a small protein called SUMO-1 modifies the mutated Huntingtin protein (Htt) linked to the disease, changing its chemical properties and making it more toxic. In addition, they found that drugs called HDAC inhibitors, which were developed for cancer chemotherapy, were able to prevent neuron damage in fruit flies carrying mutated Htt proteins.

Marsh is professor of developmental and cell biology in the School of Biological Sciences, and Thompson is associate professor of psychiatry and human behavior, and of biological chemistry in the School of Medicine. Namita Agrawal, Judit Pallos, Natalia Slepko, Barbara Apostol and Laszlo Bodai of UCI, and Wen Chang and Ann-Shyn Chiang of the National Tsing Hua University in Taiwan contributed to the study. The Heredity Disease Foundation, the Cure HD Initiative, the Huntington's Disease Society of America and the National Institutes of Health provided funding support.

About the study

Huntington's disease is caused by an expansion of a repeated stretch of the amino acid glutamine within the Huntingtin protein (Htt). At least eight other neurodegenerative disorders also are 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 then they would individually and at levels in which their toxicity is lessened.

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).

"These results provide a proof-of-principle approach to test combinations of compounds shown singly to have therapeutic efficacy in flies and in mammalian models of Huntington's disease," Thompson said. "In addition, they raise the possibility that these particular combinations may prove effective in future human tests."

About combinatorial drug therapies

Combinatorial drug therapies treat complex diseases in which a single drug given at an effective dose may provide some relief, but only treats one component of the disease process. These regimens are attractive because lower doses of drugs can be used in order to avoid undesirable side effects caused by high-drug concentrations that might be used if a single drug was employed. In addition, combinations of drugs that each provide some relief from symptoms might be expected to provide even greater relief when in combination. Combinatorial drug therapies are currently being used in treatments for certain cancers, AIDS and complex human diseases.

Original Press Release