(Press-News.org)
Researchers from the Shenzhen Institute of Advanced Technology (SIAT) of the Chinese Academy of Sciences (CAS) and their collaborators have developed a gene therapy strategy to selectively manipulate Parkinson's disease-affected circuitry and attenuate the core motor symptoms of Parkinson's disease in rodent and nonhuman primate animals.
The study was published in Cell on Nov. 2.
Parkinson's disease, characterized by the loss of midbrain dopaminergic neurons, is one of the most common neurodegenerative diseases in the elderly population, affecting more than 6 million people worldwide.
Dopamine receptor D1-expressing and D2-expressing medium spiny neurons (D1-MSN and D2-MSN, respectively) constitute 90% of neurons in the striatum. Both D1-MSN and D2-MSN receive dopaminergic innervation from the substantia nigra pars compacta (SNc), yet play opposing roles in movement control.
D1-MSNs that project to the globus pallidus internal segment (GPi) and substantia nigra pars reticulata (SNr) constitute the direct pathway and promote movement. In contrast, D2-MSNs that project to the globus pallidus external segment (GPe) form the indirect pathway and mediate movement inhibition.
In Parkinson's disease, dopamine depletion causes hypoactivity of the direct pathway and hyperactivity of the indirect pathway, resulting in various motor symptoms.
Levodopa (L-Dopa)-based treatment, which helps to restore the dopamine system's function, is the mainstay therapy for Parkinson's disease. Unfortunately, almost all patients given long-term L-Dopa treatment suffer from motor complications (e.g., motor fluctuations and dyskinesia). Thus, precise, efficient and stable treatments are greatly needed.
Since the SNr receives dense projection from the D1-MSNs and no projection from the D2-MSNs, the researchers proposed that D1-MSNs could be selectively labeled by injecting highly efficient retrograde adeno-associated virus (AAV) into the SNr and then be exclusively manipulated by introducing neuronal activity-regulating elements in the retrograde AAV.
To achieve the above objectives, they developed a novel AAV capsid, AAV8R12, for efficient retrograde labeling of the D1-MSN in the striatum as well a new promoter G88P2/3/7 with strong D1-MSN activity. With a chemogenetic effector rM3Ds to match systemic administration of the activation drug, this gene therapy strategy was able to specifically activate D1-MSN and thus drive the D1-MSN-mediated direct pathway.
Typical motor symptoms such as bradykinesia, rigidity, and tremor were greatly improved in primate models with Parkinson’s disease after applying the circuit-specific approach targeting D1-MSNs. For example, bradykinesia was greatly reduced, tremor was completely eliminated, and motor skills were restored.
Unlike L-Dopa treatment which non-specifically activates the dopamine system in both the brain and peripheral organs, this new approach precisely manipulates the D1-MSN-mediated direct pathway.
In addition to its therapeutic effectiveness, this circuit-manipulating gene therapy has faster onset and longer duration compared to L-Dopa treatment. The alleviation of symptoms after a single drug administration lasts longer than 24 hours compared to a typical 6-hour therapeutic window for L-Dopa. Motor complications such as dyskinesia shown after L-Dopa treatment were absent after applying the gene therapy over an extended period (i.e., over eight months).
Besides showing potential for treating Parkinson's disease, this circuit-manipulating gene therapy paves the way for future development of targeted, circuit-based therapeutic strategies for other brain disorders.
END
Women who receive a false positive mammography result are more likely to develop breast cancer over the subsequent 20 years, report researchers from Karolinska Institutet in a study published in JAMA Oncology. The risk is highest for women aged between 60 and 75 and who have low breast density.
In global terms, breast cancer is the most common form of cancer among women, and screening is an important tool for catching women with a tumour at the earliest possible stage. In Sweden, all women between ...
About The Study: In this study of 274 midlife women, greater posttraumatic stress disorder (PTSD) symptoms were associated with higher carotid atherosclerosis and, among women who were APOEɛ4 carriers, greater brain small vessel disease and poorer cognitive performance. These findings point to the adverse implications of PTSD symptoms for cardiovascular and neurocognitive health among women in midlife, particularly for women who are APOEɛ4 carriers.
Authors: Rebecca C. Thurston, Ph.D., of the University of Pittsburgh, is the corresponding author.
To access the embargoed ...
About The Study: The findings of this study suggest that the risk of developing breast cancer after a false-positive mammography result differs by individual characteristics and follow-up. These findings can be used to develop individualized risk-based breast cancer screening after a false-positive result.
Authors: Xinhe Mao, M.Sc., of the Karolinska Institutet in Stockholm, is the corresponding author.
To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/
(doi:10.1001/jamaoncol.2023.4519)
Editor’s Note: Please ...
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When people who had elevated blood pressure participated in an eight-week mindfulness-based blood pressure reduction program for the study, they significantly improved their scores on measures of self-awareness and adherence to a heart-healthy diet compared to a control group. The results were published in JAMA Network Open.
“Participants ...
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Alpelisib, the first drug targeting PI3Ka, was approved for use in the United States four years ago, but cancers with mutated PIK3CA eventually develop resistance to the medication.
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CLEVELAND—Case Western Reserve University has established an Institute for Glial Sciences to advance research of glial cells and their critical role in the health and diseases of the nervous systems, including multiple sclerosis, Alzheimer’s, pediatric leukodystrophies, Autism spectrum disorders, Parkinson’s disease and cancer.
Housed within the Case Western Reserve School of Medicine’s Department of Genetics and Genome Sciences, the new institute will be directed by Paul Tesar, the Dr. Donald and Ruth Weber Goodman Professor of Innovative ...
