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Research Shows New Therapies Targeting Parkinson’s Disease May Cause Harm

Findings could change treatment paradigm (Mar. 20)

Researchers at NorthShore University HealthSystem in San Diego, California, and at the Mayo Clinic in Rochester, Minnesota, have found genetic and clinical evidence that therapies targeting the expression of alpha-synuclein — a gene whose function is involved in the development and progression of Parkinson’s disease (PD) — may accelerate disease progression and increase the risk of physical incapacitation and dementia. If replicated, the findings will have profound implications for therapies under development for PD.

Alpha-synuclein is a major component of Lewy bodies — a characteristic brain cell abnormality that occurs in all cases of PD. Since its discovery as a cause of familial PD nearly 20 years ago, alpha-synuclein has been the focus of intensive efforts by researchers working to definitively characterize the protein’s role in idiopathic PD and its potential as a target for neuroprotective therapies. It has also been the focus of efforts to develop a molecule that suppresses the protein’s function. A vaccine that targets alpha-synuclein (reducing alpha-synuclein levels) is currently in phase I clinical trials, and a number of molecules that target the protein for reduction are in advanced stages of preclinical development.

“For the first time, we observed that while over-expression of alpha-synuclein increases the risk for developing Parkinson's disease, conversely, under-expression is associated with worse motor and cognitive outcomes after the disease starts,” said lead author Katerina Markopoulou, MD, PhD. “This raises concerns about the efficacy and safety of therapies designed to reduce alpha-synuclein expression in Parkinson's disease.”

The researchers followed 1,098 Mayo Clinic patients for nearly 15 years (median follow-up period: 8 years), and sequenced the patients’ DNA to determine the presence of gene variants that regulate how much alpha-synuclein protein is made. The investigators studied the association of these gene variants with patients’ survival that was free of severe motor and cognitive disabilities. Patient outcomes were measured by telephone interviews.

The scientists found that patients who had the reduced-expression genotype had a 23% greater risk of becoming wheelchair-dependent or of developing dementia.

“This is the first large genetic-association study of alpha-synuclein and longitudinal outcomes in Parkinson’s disease,” said Mayo Clinic neurologist Eric Ahlsberg, MD, PhD. “If replicated, this research may change the treatment paradigm focused on alpha-synuclein reduction for Parkinson's disease.”

Source: Mayo Clinic; March 20, 2013.

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