Advances in Genetic Parkinson Disease With Alpha-Synuclein

Andrew Siderowf, MD

In Parkinson disease (PD), researchers and clinicians are constantly on the search for effective therapies, as there are no approved disease-modifying therapies currently available. There is ongoing research in areas of genetically-influenced PD, such as investigating anti-alpha synuclein and anti-inflammatories approaches.

Recently, a published cross-sectional study in The Lancet Neurology, sponsored by The Michael J. Fox Foundation for Parkinson’s Research (MJFF), used an alpha-synuclein seed amplification assay (αSyn-SAA) technique to accurately diagnose PD.¹ The research was co-led by authors Andrew Siderowf, MD, director, PD and movement disorders center at the University of Pennsylvania, and Luis Concha, PhD, director, research and development at Amprion.

Data on αSyn-SAA was collected from a total of 1123 participants from the Parkinson’s Progression Markers Initiative (PPMI) cohort, including patients with a diagnosis of PD and at-risk patients with gene variants (GBA and LRRK2) linked to the disease. In the large-scale analysis, αSyn-SAA was shown to differentiate PD from controls with a sensitivity of 88% and specificity of 96%.

In a recent interview with NeurologyLive®, Siderowf, who also serves as a professor of neurology at the University of Pennsylvania, sat down to talk about the current trends in research for patients with PD. He also talked about potential new emerging therapeutics in the field such as neuromodulation and the foscarbidopa/foslevodopa pump. As for research, he briefly mentioned the PPMI cohort study and identified biomarkers of the disease. Furthermore, Siderowf shared his thoughts on the unmet needs patients are currently facing and need to shift focus in the landscape of care.

NeurologyLive®: What does the research landscape look like for therapeutics in Parkinson disease? What should patients look forward to?

Andrew Siderowf, MD: Neuromodulation is available to patients who have been diagnosed with PD and are seeking better treatments. It is the big story this year, whether that’s neuromodulation from high frequency focus ultrasound. There was a paper in the New England Journal of Medicine showing that this approach is safe and effective for PD. Also, research has looked at existing deep brain stimulation and improvements in the stimulators, both with more flexible programming and the potential for smart devices that might be responsive to brain activity and modulate the program based on the minute to minute needs that patients have. I think this is an important and emerging story that affects patients with PD right now.

This year, I think we were all hoping that the foscarbidopa/foslevodopa pump, carbidopa/levodopa, would be approved, but the FDA declined to approve it in March and asked for more information. I think the community and the patients especially are hopeful that this process won't be that protracted and the pump will be available for clinical use in the near future. It's important to note that it will be helpful as an adjunct to therapy. But in a clinical trial with the pump last year, published in Lancet Neurology, there were a substantial amount of skin reactions. I think that'd be something that we have to keep an eye on. It's not going to be an unmitigated win, but I think it will be a nice addition. We're looking forward to seeing it come out. That's the main new therapy that we're looking at coming out this year. There are new, more extended-release forms of carbidopa/levodopa, which we expect next year, but it's not out yet. The big story is in the neuromodulation.

What are important areas of research for genetically determined PD?

The two big areas of research that I always point to is on genetically determined PD either with GBA or LRRK2. There are a number of companies that are working on experimental therapeutics in those areas. They're either all early in phase 3, very late in phase 3, or earlier. These things aren't right around the corner, but they're being tested. More specifically, the Biogen and Denali partnership for LRRK2 inhibitors in later phase testing, and there are other companies are working both to mitigate the effects of LRRK2 and GBA. These are important areas of research.

The other area that's important is the therapy that targets alpha-synuclein. This has been sort of a mixed bag, there are 2 trials that ran out last fall, SPARK and PASADENA, sponsored by Biogen Roche, respectively. They both are testing of anti-alpha-synuclein antibodies, targeting slightly different components of alpha synuclein aggregates, but nonetheless, similar in their global mechanism. Both were negative on their primary outcome. PASADENA was positive on some key secondary outcomes, but Spark was negative across the board.

What are your current views on the hypothesis of synuclein being the cause of PD?

The hypothesis that synuclein is an important part of what causes PD, and that removing alpha-synuclein would be beneficial in terms of preventing disease progression, is still reasonable and still supported by a broad base of preclinical evidence. One conclusion you could draw is that the theory is okay, but the drugs that were tested didn't work at the doses that were tried. Other approaches to removing synuclein are tried to mitigate the effect of synuclein spread across the brain leading to PD progression, and are still very much on the table as being leading candidates for PD therapeutics.

The third area, which I think is starting to seeing see a little bit more of recently, is anti-inflammatories. There's an idea that there's this misregulated inflammatory mechanisms in PD, and if you could approach this problem, this would reduce the secondary damage that's caused by PD pathology, reducing inflammation and the inflammation inducing additional pathology. You could break this cycle, and you would slow down progression of PD. These anti-inflammatories are another area of intense research investigation, and hopefully it will bear some fruit.

What were the advantages of the alpha-synuclein seed amplification study?

We're very pleased with the results of the alpha-synuclein seed amplification study that came out of PPMI and it builds on half a decade of earlier research in this area, starting in 2017. The advantages to our study were that it was a very large and a very well characterized patient cohort. It also extended what was known by showing rates of positivity in different groups of premanifest or preclinical patients, as well as in subgroups based on clinical features, especially hypoxemia and genetic, especially LRRK2 and GBA. In addition to that, I think that there's intense effort to find this nucleon pet tracer, and there are a number of groups working on this. It's not inconceivable that we'll see better MSA [multiple system atrophy] tracers, which were first reported last year, in the peer reviewed literature soon. It's still in the development stages, but understanding in the field is there are a number of groups working on super tracers that would detect Lewy pathology. Hopefully we'll see readouts from some of these groups in the next year as well.

What are the unmet needs of patients with PD, and how should the landscape of care shift its focus?

In terms of unmet needs, they are quite the same as they've always been. We talk a lot about early detection and prodromal detection, and prevention, but the disabling features of PD occur in the second and third decades of disease. After patients have been diagnosed for quite some time, they start to develop disabling problems with unresponsiveness to foslevodopa, postural instability, cognitive impairment, and psychosis. These things are still unmet needs. While we focus a lot of attention on prodromal PD and preventing progression in early PD, symptomatic treatment for late PD, or prevention in the middle stages of PD that would prevent the disabling leader features, is still on the table. I think there's just not a consensus about how to implement this in terms of clinical trials. In other words, how to implement neural protection in the middle stages of PD.

Transcript edited for clarity.

REFERENCES
1. Michael J. Fox Foundation Announces Significant Breakthrough in Search for Parkinson’s Biomarker. News Release. The Michael J. Fox Foundation for Parkinson’s Research. Published April 12, 2023. Accessed April 18, 2023. https://www.michaeljfox.org/research-news