Parkinson’s cure ‘inevitable’ after biomarker breakthrough

The Michael J. Fox Foundation for Parkinson’s Research (MJFF) has announced what it says is the ‘most significant breakthrough’ in the search for Parkinson’s biomarkers: a biologic test for Parkinson’s disease. This test exhibits high diagnostic accuracy, differentiates molecular subtypes, and detects disease in individuals before cardinal movement symptoms appear.

A paper about the test was published in The Lancet Neurology journal by leaders of Parkinson’s Progression Markers Initiative (PPMI), the MJFF-sponsored study of Parkinson’s biomarkers.

The new Parkinson’s test, known as the seed alpha-synuclein (αSyn-SAA) amplification test, marks the research ability to biologically define Parkinson’s disease, offering important tools for clinical trial design and assessment of treatment effects, and for early detection of the disease. disease pathology.

The PPMI authors say the test detects synuclein pathology, one of the two biologic features of Parkinson’s disease (along with dysfunction of dopaminergic transport, which can be visualized using DaTScan). As a result, for the first time since James Parkinson first characterized the disorder in 1817, researchers and clinicians can use biology (as opposed to clinical judgment and patient-reported results) to objectively identify, define, and monitor Parkinson’s, based on cellular pathology in the body. .

A new era in Parkinson’s disease research

“The validation of this biomarker launches a new biological era in Parkinson’s research,” said Kenneth Marek, PPMI principal investigator, president and senior scientist at the Institute for Neurodegenerative Disorders.

“By using αSyn-SAA, we have unlocked a new understanding of Parkinson’s, which will change every aspect of drug development and ultimately clinical care. We will quickly be in a position to test new therapies in the right populations, target the right therapies to the right patients at the right time, and launch studies of agents that have the potential to prevent Parkinson’s disease entirely. This is what PPMI was built for, and we are very grateful to the thousands of study participants whose contributions have made this important moment possible.”

The paper, co-led by Andrew Siderowf, PPMI investigator and director, Center for Parkinson’s Disease and Movement Disorders at the University of Pennsylvania and Luis Concha, director, research and development at Amprion, outlines the results of αSyn-SAA from more than 1,100 PPMI participants including individuals with Parkinson’s disease, those with genetic and/or clinical risk factors but not diagnosed with Parkinson’s, and control volunteers.

High sensitivity

Large-scale analyzes at PPMI confirmed previous reports—including from MJFF-funded work—that αSyn-SAA could differentiate Parkinson’s from control volunteers with 88% sensitivity and 96% specificity.

As an objective and reliable biomarker of Parkinson’s, αSyn-SAA will significantly reduce risk for the industry to invest in the development of potential blockbuster therapies, including preventive agents, and increase the speed and efficiency with which these therapies can be developed, tested, and brought to market.

Using αSyn-SAA, it will be possible to establish objective end points for clinical trials of Parkinson’s treatment, ensure study participants present appropriate pathology, and detect therapy-induced changes in their status. This is already changing the design of clinical trials and could drive greater pharmaceutical and biotechnology investment in the space — creating more “shots on target” to benefit people at every stage of disease.

The biological subtypes of Parkinson’s disease are related to genetic and clinical factors

The authors report findings related to olfactory deficits, or loss of smell (a lasting and significant loss of smell is a common symptom of Parkinson’s that is often seen years before diagnosis) and carrying mutations in the Parkinson’s-associated LRRK2 gene.

• The test accurately diagnoses the disease in 99% of people with smell loss and sporadic Parkinson’s (without a known causal genetic mutation).
• The proportion of positive results – as high as 68% – is lower in people with Parkinson’s and the LRRK2 mutation.
• Positive results were lower in people with sporadic Parkinson’s without olfactory deficits (78%).
• For people with Parkinson’s, LRRK2 mutations and normal ability to smell are even less likely to show a positive test result. This is especially the case with women; only 12.5% ​​of women in this population showed synuclein pathology on testing.
• In persons with Parkinson’s enrolled at PPMI who consented to post-mortem examination and who had passed since joining the study, all with positive test results demonstrated the characteristic pathology of alpha-synuclein aggregation in brain cells; the only PD participants who did not test positive were carriers of the LRRK2 mutation with preserved olfaction.

The researchers say the results suggest that not all cases of Parkinson’s clinical symptoms are associated with the accumulation of alpha-synuclein aggregates as detected by this assay, and that carriers of the LRRK2 variant, in particular, may not exhibit this pathology.

Parkinson’s disease: New avenues of inquiry

This opens new avenues of investigation toward treatments to benefit more people with PD. It will also allow deeper studies of the cellular pathways and cascades that occur in Parkinson’s associated LRRK2, some of which may protect against synuclein dysfunction and Parkinson’s toxicity. MJFF says this could lead to breakthroughs to benefit everyone with Parkinson’s, not just those who carry the genetic mutation. Three therapies that target dysfunction in the LRRK2 pathway are currently in clinical trials.

Development of a Parkinson’s disease biomarker test

αSyn-SAA was developed when the MJFF neuroscience PhD staff approached researchers at the University of Texas working on a seed amplification test in Alzheimer’s. The foundation is offering funding to experiment with developing an alpha-synuclein test using PPMI cerebrospinal fluid samples.

The University of Texas team that developed the assay has launched a biotech company, Amprion, which partnered with PPMI on αSyn-SAA analysis. The company has commercialized the test as the SYNTap test, which is available to order by doctors, for people showing symptoms of Parkinson’s or related disorders.

When the test is positive, a person may have Parkinson’s or an alpha-synuclein-related disorder, such as dementia with Lewy bodies (DLB) or multiple system atrophy (MSA). The test itself cannot differentiate between these diseases. It also may not be covered by insurance. However, with respect to a doctor’s examination, the test may help support a certain diagnosis.

“The Michael J. Fox Foundation has always recognized the undeniable need for Parkinson’s disease biomarkers, and relentlessly pursued them as a mission critical goal,” said Deborah W. Brooks, chief executive of MJFF (and PPMI control volunteer at the University of Pennsylvania since 2010).

“It would be difficult to overstate the implications of this discovery. With development and scaling, αSyn-SAA can usher in an era of objectively and biologically defined Parkinson’s disease — revolutionizing every aspect of research and care.”

Parkinson’s cure “inevitable”

Michael J. Fox said: “There are many ways I am involved with the work of the Foundation, but I arrived at these results first and foremost as a Parkinson’s patient. I am deeply moved by this breakthrough and eternally grateful to the researchers, study participants, and funders who have worked to get us this far. When we started PPMI, we weren’t fishing – we were chasing whales. Now, here we are. Together, we created the inevitable cure for Parkinson’s.”

About PPMI

MJFF launched the Progressive Parkinson’s Marker Initiative in 2010 at 18 clinical sites in the US and Europe. A longitudinal observational study, PPMI has built a robust dataset and biosample library, which is shared with the wider research community in real time for ongoing discovery and validation studies. To date, the study has enrolled nearly 2,000 participants and is actively enrolling Parkinson’s patients, at-risk individuals, and control volunteers at 51 clinical sites worldwide. Study data was downloaded by researchers worldwide for independent studies an average of 2,200 times a day.

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