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Peer-reviewedCC BY-NC 4.0Journal of Parkinson's Disease

Regulatory endorsement for the application of α-synuclein seed amplification assay as a susceptibility and risk biomarker for clinical trials targeting synucleinopathies

  • Diane Stephenson1
  • Luis Concha-Marambio2
  • Tom Lanz3
  • Kalpana Merchant4
  • Kathrin Brockmann5
  • Nicholas King1
  • Laura Carrillo1
  • Anne Pedata1
  • Harsha Kocherla6
  • Samantha J Hutten7
  • on behalf of the Critical Path for Parkinson's Consortium
7 affiliations
  1. 1Neuroscience Department, Critical Path Institute, Tucson, Arizona, USA
  2. 2Amprion Inc., San Diego, USA
  3. 3Drug Safety Research & Development, Pfizer Inc, Groton, CT, USA
  4. 4Northwestern Univ, TransThera Consulting Co, Portland, USA
  5. 5Center of Neurology, Department of Neurodegenerative Diseases, German Centre for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany
  6. 6Novartis AG, Basel, Switzerland
  7. 7The Michael J. Fox Foundation for Parkinson's Research, New York, NY, USA
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Abstract

Transformation in the neurosciences in biomarkers is enabling novel therapeutic strategies targeting earlier stages of disease prior to onset of clinical symptoms. Emerging progress in the area of synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB) have significant implications for clinical trials. Misfolded α-synuclein aggregates (syn-seeds) propagate by templated misfolding of native α-synuclein, driving disease spread. The advent of the α-synuclein seed amplification assay (syn SAA) now enables highly sensitive and specific detection of syn-seeds in cerebrospinal fluid (CSF), allowing in vivo identification of underlying α-synuclein pathology, including in individuals prior to the onset of motor symptoms.

To support regulatory alignment, the Critical Path Institute's Critical Path for Parkinson's (CPP) consortium compiled and evaluated the totality of scientific evidence in the area of syn SAA as an in vivo measure of misfolded alpha synuclein in CSF and submitted it to the U.S. Food and Drug Administration (FDA) in a request for a Biomarker Letter of Support (LoS). Within three months of submission, the FDA issued a LoS endorsing CSF syn SAA as a susceptibility and risk biomarker for use in clinical trials targeting α-synuclein–related neurodegenerative diseases, enabling enrichment of participants with underlying pathology and reducing trial risk. These data have enabled the development of biological classification frameworks for synucleinopathies that define disease based on molecular pathology rather than clinical symptoms alone.

This review summarizes the regulatory-grade evidence supporting syn SAA and discusses its implications for biologically driven clinical trial design and early-intervention strategies.

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Cite

BibTeXRIS
BibTeX
@article{stephenson2026regulatory,
  title = {{Regulatory endorsement for the application of α-synuclein seed amplification assay as a susceptibility and risk biomarker for clinical trials targeting synucleinopathies}},
  author = {Diane Stephenson and Luis Concha-Marambio and Tom Lanz and Kalpana Merchant and Kathrin Brockmann and Nicholas King and Laura Carrillo and Anne Pedata and Harsha Kocherla and Samantha J Hutten and on behalf of the Critical Path for Parkinson's Consortium},
  journal = {Journal of Parkinson's Disease},
  year = {2026},
  month = jul,
  doi = {10.1177/1877718x261463936},
  url = {https://doi.org/10.1177/1877718x261463936},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - Regulatory endorsement for the application of α-synuclein seed amplification assay as a susceptibility and risk biomarker for clinical trials targeting synucleinopathies
AU  - Diane Stephenson
AU  - Luis Concha-Marambio
AU  - Tom Lanz
AU  - Kalpana Merchant
AU  - Kathrin Brockmann
AU  - Nicholas King
AU  - Laura Carrillo
AU  - Anne Pedata
AU  - Harsha Kocherla
AU  - Samantha J Hutten
AU  - on behalf of the Critical Path for Parkinson's Consortium
PY  - 2026
DA  - 2026/07/24
JO  - Journal of Parkinson's Disease
DO  - 10.1177/1877718x261463936
UR  - https://doi.org/10.1177/1877718x261463936
AB  - Transformation in the neurosciences in biomarkers is enabling novel therapeutic strategies targeting earlier stages of disease prior to onset of clinical symptoms. Emerging progress in the area of synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB) have significant implications for clinical trials. Misfolded α-synuclein aggregates (syn-seeds) propagate by templated misfolding of native α-synuclein, driving disease spread. The advent of the α-synuclein seed amplification assay (syn SAA) now enables highly sensitive and specific detection of syn-seeds in cerebrospinal fluid (CSF), allowing in vivo identification of underlying α-synuclein pathology, including in individuals prior to the onset of motor symptoms.  To support regulatory alignment, the Critical Path Institute's Critical Path for Parkinson's (CPP) consortium compiled and evaluated the totality of scientific evidence in the area of syn SAA as an in vivo measure of misfolded alpha synuclein in CSF and submitted it to the U.S. Food and Drug Administration (FDA) in a request for a Biomarker Letter of Support (LoS). Within three months of submission, the FDA issued a LoS endorsing CSF syn SAA as a susceptibility and risk biomarker for use in clinical trials targeting α-synuclein–related neurodegenerative diseases, enabling enrichment of participants with underlying pathology and reducing trial risk. These data have enabled the development of biological classification frameworks for synucleinopathies that define disease based on molecular pathology rather than clinical symptoms alone.  This review summarizes the regulatory-grade evidence supporting syn SAA and discusses its implications for biologically driven clinical trial design and early-intervention strategies.
SN  - 1877-7171
SN  - 1877-718X
ER  -