NEW YORK (360Dx) – A lipid-based ELISA that captures and quantifies the alpha-synuclein protein biomarker in blood could provide an earlier diagnosis than is currently possible for Parkinson's disease, according to the test's developers at Hebrew University of Jerusalem.
Importantly, the assay could enable the development of treatments for early stages of the disease, which has been exceptionally difficult to diagnose, Ronit Sharon, a senior researcher at Hebrew University's Institute for Medical Research Israel-Canada who supervised the development of the assay, said in an interview.
The researchers said that they believe their approach could lead not only to earlier detection, but also to a better way to track Parkinson's progression in patients and, eventually, their response to therapy.
"Once we know, by detecting it earlier, who is developing Parkinson's disease, companies may be encouraged to develop therapeutics that can better interfere with its progression," Sharon said.
Sharon noted that Parkinson's patients sometimes suffer from symptoms "that are unrelated to the central nervous system in the brain" and that are revealed in peripheral systems, and blood is therefore "a good place to look for candidate biomarkers for early diagnosis."
Sharon said that the ELISA developed by her and her colleagues could be available within about a year to clinicians, researchers, and investigators working in drug companies.
Yissum Research Development, the technology transfer arm of Hebrew University of Jerusalem, holds the patents on the technology, and it has an agreement to provide Integra Holdings, a healthcare investment company, with an exclusive first right to evaluate innovations and IP emerging from the school. Integra is raising capital with a view to further developing and commercializing the assay as a diagnostic kit.
While the availability of a diagnostic test would be a step forward in the fight against Parkinson's, it would not immediately help patients, Sharon said, adding that because effective diagnostic tests haven't been available to help clinicians provide early detection, effective treatments haven't been available either to prevent the progression of the disease.
Clinicians, currently, do not know how to completely stop the progression of Parkinson's. Even with the ability to conduct an early diagnosis, Parkinson's would continue to progress, and clinicians — without better therapies — could only offer lifestyle advice that might slow its progression, Sharon noted.
Ali Torkamani, the director of genome informatics at Scripps Translational Science Institute who is working to improve screening accuracy of Parkinson's disease, noted that many of the signs of early Parkinson’s Disease are subtle and similar to other neurodegenerative disorders.
"Early diagnosis of Parkinson’s disease has the potential to help prioritize therapy early, slow disease progression, and delay long-term neurological damage," he said. With reference to the assay being developed at Hebrew University and ongoing work at STSI to improve upon the accuracy of screening for Parkinson's, he added that "Novel diagnostics are needed to enable early detection of disease and to potentially improve health outcomes."
The Hebrew University assay is specifically designed to identify α-synuclein in the blood by leveraging a biochemical property of the protein that enables it to bind lipid membranes. During binding, a biological structure emerges that "is better recognized by specific antibodies," providing greater sensitivity than other assays in development for Parkinson's, Sharon said.
Their ELISA identifies the cellular secretion of alpha-synuclein, a biomarker that's closely associated with tissues in which Parkinson’s disease can be detected, and with the neurological pathways along which the disease travels and causes its characteristic symptoms.
As part of a clinical study, the team is analyzing samples from a patient cohort, including those with moderate and severe Parkinson's disease and control cases. They've tested more than 100 non-blinded samples in collaboration with Hadassah Medical Center Neurology Department, Sharon said. The Michael J. Fox Foundation and the US National Institutes of Health, through a program called BioFind, have teamed with Hadassah's Neurology Department to provide clinical samples for the study.
Results thus far have validated that the lipid-based ELISA differentiates patients who have Parkinson's from healthy people, with specificity and sensitivity levels greater than 85 percent, said Suaad Abd-Elhadi, a Ph.D. student at Hebrew University, who is leading the development of the assay under the supervision of Sharon.
In 2015, Sharon, Abd-Elhadi, and colleagues described an investigation published in the journal Scientific Reports in which they reported what they believed to be "the first evidence for an association between [alpha-synuclein] expressed in red blood cells and pathogenic mechanisms involved in [Parkinson's disease].
They followed that up with a study published in the Journal of Analytical and Bioanalytical Chemistry in September 2016 that described the use of a lipid-ELISA to determine the total levels of alpha-synuclein in whole blood cells, cerebrospinal fluid, and saliva.
Upon the expected completion of the current clinical study in a few months, the researchers will be able to again calculate the test's sensitivity and specificity by including results from the blinded portion of the study.
The alpha-synuclein protein used in the studies is of great interest to Parkinson's researchers because it is a major constituent of Lewy bodies — protein clumps that are the pathological hallmark of Parkinson's disease.
The protein causes Parkinson's in the brain when it is mutated or overexpressed, Sharon said, adding that in developing and validating the ELISA test, they have observed what others have reported — that "alpha-synuclein in the blood is a potential biomarker for [Parkinson's] disease."
Parkinson’s, the second most common neurodegenerative disorder in humans after Alzheimer’s, is typically characterized by changes in motor control and is manifested by tremors and shaking, and it can also include non-motor cognitive and behavioral symptoms. However, its symptoms are extremely challenging to pin down and can vary from day to day, which have flummoxed drug firms trying to develop therapies for the ailment, Sharon said.
The combined direct and indirect cost of Parkinson’s, including treatment, social security payments and lost income from inability to work, is estimated to be nearly $25 billion per year in the United States alone, according to the Parkinson's Disease Foundation, and more than 10 million people worldwide are living with the disease. Medication costs about $2,500 a year, and therapeutic surgery costs around $100,000 dollars per patient.
In the face of these challenges, a few organizations are looking to bring a Parkinson's disease test to the marketplace or have hereditary panels adopted. In April, the US Food and Drug Administration granted premarket authorization for 10 genetic health risk reports, including a test for Parkinson's risk, from consumer-focused testing company 23andMe.
Also, San Francisco-based Invitae offers a hereditary Parkinson’s disease panel to clinicians that analyzes up to 17 genes associated with the disease and its related conditions.
Additionally, numerous research projects are underway to elucidate the disease and improve diagnostic methods. The Scripps Translational Science Institute in 2016 said it was collaborating with the Michael J. Fox Foundation and Intel to launch a clinical study in an effort to improve screening accuracy.
They have launched a study, called the Genetic and Digital Diagnosis of Essential Tremor and Parkinson's Disease, that's being run through the Parkinson's Disease and Movement Disorder Center at Scripps Clinic in La Jolla.