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Sep 15, 2010 (Vol. 30, No. 16)

Parkinson Disease Research in Doldrums

Discontinuation of PD Trial Highlights Hazards Inherent in Developing Drugs for This Indication

  • Targeting Alpha-Synuclein

    The abnormal proteins present in specific brain cells of patients with several neurodegenerative diseases including Alzheimer disease (AD), Huntington disease (HD), Lewy body dementia, and PD are attracting attention as potential drug targets. Controversy still exists, however, as to whether they are the root cause of these diseases or the result of upstream events. Yet, these proteins may prove to be more promising and discrete targets for new drugs than neurotransmitter systems.

    Robert L. Nussbaum, M.D., and Christopher E. Ellis, Ph.D., pointed out, in a 2003 article in The New England Journal of Medicine, that the genetic mapping and gene-isolation tools created by the Human Genome Project greatly accelerated the rate of identification of genes involved in the rare inherited forms of PD and AD. These same tools and their more sophisticated descendents are now being used to determine the genetic contributions to the more common, multifactorial forms. They revealed alpha-synuclein as a neurotoxic in PD and believe that it may explain the pathogenesis not only of the inherited form of PD but also of the idiopathic form.

    Alpha-synuclein is a major component of the filamentous inclusions called Lewy bodies, protein clumps that are the pathological hallmark of PD. The normal function of alpha-synuclein remains unknown, although it is thought to play an important role in synaptic function or lipid binding. Synuclein usually remains in an unfolded state but is highly prone to aggregation.

    The Michael J. Fox Foundation (MJFF) has invested about $12 million to date in alpha-synuclein. It supports researchers working to characterize the protein’s role in PD, assess its potential as a target for neuroprotective therapies, and develop drugs that inhibit aggregation of synuclein filaments into clumps.

    No drugs targeting alpha-synuclein have reached the clinic, according to the MJFF. Some approved compounds, though, have been shown to stop synuclein clumping and to break up clumps in vitro. Even sirtuins are getting into the act, as investigators reported discovery of a potent sirtuin 2 (SIRT2) inhibitor that rescued alpha-synuclein toxicity and modified inclusion morphology in a cellular model of PD.

  • Need for Better Animal Models

    G. Linazasoro and colleagues at the faculty of medicine, University of the Basque Country, Leioa, pointed out that PD is a multisystemic disorder involving neurotransmitters other than dopamine. But even drugs acting on nondopaminergic systems, as in the case of vipadenant, have yet to prove their mettle.

    Additionally, compounds targeting glutamate, adenosine, noradrenaline, 5-hydroxytryptamine, cannabinoid, and opioid transmitter systems that have been assessed in human studies show negative, inconsistent, or unsatisfactory results, points out Dr. Linazasoro. Most of these drugs have been tested in two specific animal models: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys and 6-hydroxydopamine-lesioned rats.

    As in many other diseases, the leap from animal models to man is hazardous. A major funding focus of the MJFF remains developing an animal model for PD. While current PD animal models may reproduce some features of the disease, the development of truly effective and safer treatments will require animal models that represent the full spectrum of biochemical and cellular lesions characteristic of the disease.

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