Skip to main content

Immunotherapy trials in Parkinson’s disease: challenges

Main text

Parkinson’s disease (PD) is a common neurodegenerative disorder, and its incidence increases from age 60 to over 90 years, posing a serious social and economic burden on aging populations globally. Point missense mutations and gene duplication or triplication of α-synuclein gene are linked to familial PD. Genome-wide association study-linked variants of α-synuclein also contribute to the risk of sporadic PD. Exogenous expression of wild-type or mutant α-synuclein recapitulates PD-like features in various animal models. The non-amyloid component domain of α-synuclein protein comprises eight β-strands and predisposes the protein to aggregation to form fibrils. Fibrillar aggregates of α-synuclein are found in Lewy bodies (LBs), a pathological hallmark of PD. Hence targeting α-synuclein has been one of the major focuses of PD therapeutics (reviewed in [1, 2]). Both passive and active immunotherapy trials against α-synuclein have created considerable excitement and hope [3].

Lang et al. reported the results of the SPARK trial that early-stage PD patients received Cinpanemab (a monoclonal antibody that preferentially binds to aggregated α-synuclein at the N-terminal of the protein to promote clearance of extracellular α-synuclein, mitigating pathological consequences [4]) experienced similar progression rate of symptoms compared with placebo up to 72 weeks [5]. In parallel, Pagano et al. reported the findings from the PASADENA study where Prasinezumab (a monoclonal antibody directed against aggregated α-synuclein at the C-terminal of the protein, which may attenuate neurodegeneration by blocking the spread of pathogenic α-synuclein between neurons [6]) failed to slow down the PD disease progression over 52 weeks [7]. Consistently, dopamine transporter imaging with single-photon-emission computed tomography (SPECT) showed little differences between the control group and treated group in both the trials [5, 7].

These clinical trials were preceded by robust findings using Cinpanemab and Prasinezumab in preclinical rodent models, where significant improvement of PD-like phenotypes has been observed [6, 8]. Phase I clinical trials in healthy subjects and patients with PD found Cinpanemab/α-synuclein complex formation in plasma [9] and dose-dependent reduction of serum α-synuclein levels by Prasinezumab [10]. What could have accounted for these divergent outcomes? The susceptibility and compensatory mechanisms pertaining to the pathogenesis of PD in animal models differ from those in humans. In addition, both genetic and toxin-induced animal models involve either artificial overexpression of the genes or chemical induction over a short period of time, events that may not reflect the actual situations in the human brain. Patient-derived induced pluripotent stem cells (iPSCs) may be differentiated into neurons/midbrain organoids with pathological features, including LB-like inclusions, thus better recapitulating the pathological changes [11]. These human models together with nonhuman primate models can be tested in future preclinical trials.

Placebo-related improvements have been observed in PD clinical trials and it may not diminish at 6 months of follow-up [12]. In addition, perceptions of medication cost were capable of altering the placebo response in a PD clinical study [13]. In the studies by Lang et al. and Pagano et al., it is unclear if perceptions of being involved in a state-of-art monoclonal antibody clinical trial have created a more profound placebo effect. A longer follow-up period may help to rule out this possibility.

Both clinical trials recruited the early-stage PD patients, as the downstream pathological cascades in the late-stage PD may already be irreversible even if the inceptive pathogenic drivers are arrested. However, owing to the mechanisms of neural compensation, there is usually 50–60% of DA neuron loss in the substantia nigra of the diagnosed PD patients [14]. The vicious cascades may have been tiggered in the surviving neurons, and therefore therapeutics may be doomed to fail. Future clinical trials may include subjects who are at prodromal stage of PD which could be selected out using criteria developed by the International Parkinson and Movement Disorder Society (MDS), including clinical features, such as rapid eye movement sleep behavior disorder (RBD) and olfactory dysfunction [15].

Over two centuries of research has reached the consensus on the PD pathogenesis that various factors/pathways trigger the pathological events that eventually lead to the disease [1]. If α-synuclein aggregation is not the critical downstream process, targeting it with α-synuclein monoclonal antibodies may ultimately not be effective for the general PD population. Instead, only a sub-group of patients associated with “high α-synuclein load” may benefit from α-synuclein monoclonal antibodies and should be pre-selected for the clinical trials of such therapeutics, particularly carriers of α-synuclein risk variants/mutations and those with high polygenic risk scores in the SNCA gene. Moreover, we will need better quantitative measures to evaluate different α-synuclein forms. Detection of α-synuclein oligomerization/aggregation in cerebrospinal fluid using protein misfolding cyclic amplification (PMCA) or real-time quaking-induced conversion (RT-QuIC) could be potential options. To address the heterogeneity of PD pathogenesis, a cocktail therapy that targets the core upstream pathogenic pathways together with α-synuclein immunotherapy may be a consideration for future trials.

In targeted immunotherapy, perhaps clinical assessment and imaging dopamine integrity alone may not be enough. Motor assessment scales (such as UPDRS) may not be an optimal clinical assessment due to its intrinsic weakness, including inter-rater consistency [16]. Functional imaging (such as SPECT) may reflect the nigrostriatal degeneration, but not improved pathological changes in the neurons which may experience better outcome in the long run. Thus, assessment of the burden of α-synuclein aggregation with the aid of iPSC-derived neurons and α-synuclein neuroimaging probes may be able to capture the difference in the clinical outcomes.

In summary, while the SPARK [5] and PASADENA [7] studies did not demonstrate efficacy of α-synuclein monoclonal antibodies in early PD, the results highlight the need to review potential limitations of preclinical studies and clinical trials from experimental models to endpoint assessments. The introduction of emerging technologies may help address the challenges in the α-synuclein-based immunotherapy. Despite the disappointing results, it may be premature to abandon exploring the potential of such therapeutic approaches.

Availability of data and materials

Not applicable.

Abbreviations

PD:

Parkinson’s disease

LBs:

Lewy bodies

SPECT:

Single-photon-emission computed tomography

iPSCs:

Patient-derived induced pluripotent stem cells

MDS:

International parkinson and movement disorder society

RBD:

Rapid eye movement sleep behaviour disorder

PMCA:

Protein misfolding cyclic amplification

RT-QuIC:

Real-time quaking-induced conversion

References

  1. Jankovic J, Tan EK. Parkinson’s disease: etiopathogenesis and treatment. J Neurol Neurosurg Psychiatry. 2020;91:795–808.

    Article  PubMed  Google Scholar 

  2. Grosso Jasutkar H, Oh SE, Mouradian MM. Therapeutics in the pipeline targeting alpha-synuclein for parkinson’s disease. Pharmacol Rev. 2022;74:207–37.

    Article  PubMed  Google Scholar 

  3. Tan EK, Chao YX, West A, Chan LL, Poewe W, Jankovic J. Parkinson disease and the immune system - associations, mechanisms and therapeutics. Nat Rev Neurol. 2020;16:303–18.

    Article  PubMed  Google Scholar 

  4. Bae EJ, Lee HJ, Rockenstein E, Ho DH, Park EB, Yang NY, Desplats P, Masliah E, Lee SJ. Antibody-aided clearance of extracellular alpha-synuclein prevents cell-to-cell aggregate transmission. J Neurosci. 2012;32:13454–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lang AE, Siderowf AD, Macklin EA, Poewe W, Brooks DJ, Fernandez HH, Rascol O, Giladi N, Stocchi F, Tanner CM, et al. Trial of cinpanemab in early parkinson’s disease. N Engl J Med. 2022;387:408–20.

    Article  CAS  PubMed  Google Scholar 

  6. Games D, Valera E, Spencer B, Rockenstein E, Mante M, Adame A, Patrick C, Ubhi K, Nuber S, Sacayon P, et al. Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in parkinson’s disease-like models. J Neurosci. 2014;34:9441–54.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Pagano G, Taylor KI, Anzures-Cabrera J, Marchesi M, Simuni T, Marek K, Postuma RB, Pavese N, Stocchi F, Azulay JP, et al. Trial of prasinezumab in early-stage parkinson’s disease. N Engl J Med. 2022;387:421–32.

    Article  CAS  PubMed  Google Scholar 

  8. Weihofen A, Liu Y, Arndt JW, Huy C, Quan C, Smith BA, Baeriswyl JL, Cavegn N, Senn L, Su L, et al. Development of an aggregate-selective, human-derived alpha-synuclein antibody BIIB054 that ameliorates disease phenotypes in parkinson’s disease models. Neurobiol Dis. 2019;124:276–88.

    Article  CAS  PubMed  Google Scholar 

  9. Brys M, Fanning L, Hung S, Ellenbogen A, Penner N, Yang M, Welch M, Koenig E, David E, Fox T, et al. Randomized phase I clinical trial of anti-alpha-synuclein antibody BIIB054. Mov Disord. 2019;34:1154–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jankovic J, Goodman I, Safirstein B, Marmon TK, Schenk DB, Koller M, Zago W, Ness DK, Griffith SG, Grundman M, et al. Safety and tolerability of multiple ascending doses of PRX002/RG7935, an anti-alpha-synuclein monoclonal antibody, in patients with parkinson disease: a randomized clinical trial. JAMA Neurol. 2018;75:1206–14.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Jo J, Yang L, Tran HD, Yu W, Sun AX, Chang YY, Jung BC, Lee SJ, Saw TY, Xiao B, et al. Lewy body-like inclusions in human midbrain organoids carrying glucocerebrosidase and alpha-synuclein mutations. Ann Neurol. 2021;90:490–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Goetz CG, Wuu J, McDermott MP, Adler CH, Fahn S, Freed CR, Hauser RA, Olanow WC, Shoulson I, Tandon PK, et al. Placebo response in parkinson’s disease: comparisons among 11 trials covering medical and surgical interventions. Mov Disord. 2008;23:690–9.

    Article  PubMed  Google Scholar 

  13. Espay AJ, Norris MM, Eliassen JC, Dwivedi A, Smith MS, Banks C, Allendorfer JB, Lang AE, Fleck DE, Linke MJ, Szaflarski JP. Placebo effect of medication cost in parkinson disease: a randomized double-blind study. Neurology. 2015;84:794–802.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Agid Y. Parkinson’s disease: pathophysiology. Lancet. 1991;337:1321–4.

    Article  CAS  PubMed  Google Scholar 

  15. Heinzel S, Berg D, Gasser T, Chen H, Yao C, Postuma RB. Disease MDSTFotDoPs: update of the mds research criteria for prodromal parkinson’s disease. Mov Disord. 2019;34:1464–70.

    Article  PubMed  Google Scholar 

  16. Movement Disorder Society Task Force on Rating Scales for Parkinson’s D. The unified parkinson’s disease rating scale (UPDRS): status and recommendations. Mov Disord. 2003;18:738–50.

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank Singapore Ministry of Health’s National Medical Research Council (Open Fund Large Collaborative Grant (MOH-000207) and Singapore Translational Research (STaR) Investigator Award (NMRC/STaR/0030/2018) to TEK, CS-IRG-NIG and OF-YIRG to BX) for their support.

Funding

None.

Author information

Authors and Affiliations

Authors

Contributions

E-KT and BX: study concept and design; E-KT and BX drafting and revising the manuscript; Both authors read and approved the final manuscript.

Corresponding author

Correspondence to Eng-King Tan.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xiao, B., Tan, EK. Immunotherapy trials in Parkinson’s disease: challenges. J Transl Med 21, 178 (2023). https://doi.org/10.1186/s12967-023-04012-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12967-023-04012-x

Keywords