Kathy Steece-Collier (Michigan State University)
14 Jan. 2019. Medical researchers are developing a treatment for a frequent side-effect of Parkinson’s disease drugs using a corrective RNA molecule to reverse the condition. The 5-year project at Michigan State University in Grand Rapids is funded by a $2.8 million grant from National Institute of Neurological Disorders and Stroke, part of National Institutes of Health.
A team led by neuroscience and translational research professor Kathy Steece-Collier is seeking a solution for dyskinesia, abnormal involuntary movements that resemble fidgeting or wriggling in some Parkinson’s disease patients. Dyskinesia can occur in varying degrees of intensity, but in some people becomes disruptive and even painful. Parkinson’s disease occurs when the brain produces less of the substance dopamine, a neurotransmitter that sends signals from one neuron or nerve cell to another. As the level of dopamine lowers, people with Parkinson’s disease become less able to control their bodily movements and emotions.
Dyskinesia often occurs as a complication of a levadopa, a common drug taken for Parkinson’s disease. In the body, levodopa converts to dopamine and helps reduce the disease’s symptoms. Levodopa is often combined with carbidopa to prevent levodopa from releasing prematurely, which allows for lower doses, reducing side effects such as nausea and vomiting. The occurrence of dyskinesia in some patients, however, sharply limits levodopa treatments, and as reported by Science & Enterprise in August 2017 also occurs with newer dopamine agonist implants.
In earlier research, Steece-Collier and colleagues found dyskinesia damage to neurons occurs in the striatum, part of the brain’s basal ganglia that governs voluntary movement. Neuron extensions that communicate signals called dendrites have tiny spines that interact with dopamine. While levodopa helps grow new spines on neurons in the striatum, in cases of dyskinesia, the spines cease to fully function. In addition, researchers identified a calcium channel in brain cells, called CaV1.3, as a target for therapies, since a surplus in calcium is associated with the spines’ retraction on dendrites.
“The catch is the new spines appear to not allow neurons to connect normally,” says Steece-Collier in a university statement. “In effect, you get miswiring, which can result in dyskinesia.”
Also from earlier research, including studies with lab rats, the researchers traced dyskinesia to single variation in the BDNF gene, which provides code for brain-derived neurotrophic factor protein. This protein promotes the survival and maintenance of neurons or nerve cells in the brain and spinal cord, particularly in synapses, or junctions, between nerve cells where the neuron-to-neuron communications take place. Their findings show levodopa has less effect when this one genetic variation, known as rs6265, occurs.
The Michigan State team proposes a test of synthetic RNA to correct for the variant BDNF gene. The Steece-Collier lab induced in lab rats a brain condition with the human rs6265 variation in BDNF genes. Researchers plan to transfer a synthetic form RNA with coding instructions to nerve cells into the lab rats, with a benign virus often used in gene transfers. The synthetic RNA, known as a short hairpin RNA for its molecular structure, carries instructions to CaV1.3 channels in nerve cells to reduce their calcium production.
Preliminary tests indicate the RNA transfer technique prevents development of dyskinesia in lab rats over extended periods, even in cases of high doses of levodopa, and can also reverse some dyskinesia symptoms. If these further preclinical tests are successful, the researchers plan to advance the technique to clinical trials.
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