(written with ChatGPT40, version April 2025)

1. History

1.1 Origin in Prion Research

Anle138b was originally developed in the context of prion diseases, such as scrapie, due to its ability to disrupt the formation of pathogenic protein aggregates. Prion pathologies share a common thread with other neurodegenerative conditions: the misfolding and accumulation of specific proteins. These commonalities prompted scientists to investigate whether the compound’s anti-aggregation properties might extend to alpha-synuclein in Parkinson’s disease.

1.2 Shift to Alpha-Synuclein

With growing recognition that alpha-synuclein plays a key role in Parkinson’s disease pathology, researchers turned from prion-related targets toward exploring compounds that could inhibit or modulate alpha-synuclein aggregation. Since Anle138b had shown promise in prion models, it became a candidate for blocking the misfolding and toxic clumping of alpha-synuclein in vivo.

1.3 Small Research Group

Although Anle138b has drawn attention from a few dedicated laboratories, it remains under the radar in the wider Parkinson’s research community. A core group of scientists — fewer than a dozen — have collectively published multiple studies investigating its pharmacological profile and disease-modifying potential. While their findings are promising, more independent groups must replicate these results to build a stronger consensus and move toward definitive clinical testing.

Author Affiliations (Top 10)

Leonov Andrei: MODAG GmbH / Max Planck Institute for Biophysical Chemistry

Ryazanov Sergey: MODAG GmbH

Griesinger Christian: Max Planck Institute for Multidisciplinary Sciences, Göttingen

Giese Armin: Ludwig-Maximilians-Universität München (LMU)

Kleger Armin: University Hospital Ulm

Weihofen Anja: MODAG GmbH

Bolognin Sara: : University of Trento, Italy

Wagner Gerhard: Harvard Medical School, USA

Bötzel Kai: LMU Munich

2. Key Points

2.1 Interaction of Anle138b with Alpha-Synuclein

• Mechanism: Laboratory data suggest Anle138b directly binds to alpha-synuclein aggregates, stabilizing the protein in a non-toxic conformation or preventing further aggregation.
  Recent high-resolution NMR experiments confirm that anle138b binds directly to α-synuclein aggregates in both early intermediates (oligomers) and mature fibrils. These findings expand on previous in vitro data by pinpointing molecular-level interactions that stabilize α-synuclein in a non-toxic conformation.
  Key takeaway: Anle138b physically associates with toxic assemblies of α-synuclein, supporting its proposed mode of action as an oligomer modulator.
• PET Tracer Derivative
  A derivative known as MODAG-001, structurally related to anle138b, has been tested as a potential PET tracer for imaging α-synuclein aggregates in vivo. While still at an early stage, this tracer demonstrated high affinity for oligomeric/fibrillar α-synuclein in binding assays, raising the possibility of future diagnostic tools to visualize aggregation in living patients.
  Key takeaway: Anle138b and its analogs may pave the way for companion imaging tracers that quantify α-syn accumulation in clinical settings.
• Relevance: By halting or slowing the growth of pathological alpha-synuclein fibrils, Anle138b may reduce neuronal damage and the spread of disease pathology, positioning it as a potential disease-modifying therapy.

2.2 In Vivo Evidence of Disease-Altering Action

• Animal Models: Studies in mouse models of synucleinopathies have reported that Anle138b can reduce alpha-synuclein inclusions, prevent neuronal loss, and even improve motor function.
• Neuroinflammation: Additional benefits may involve mitigation of neuroinflammatory processes, which often accompany and exacerbate protein-misfolding disorders.
• Safety Profile: So far, preclinical data indicate a tolerable safety profile, although this must be validated in large-scale clinical studies.

2.3 Efficacy Across Multiple Disease Models

• Parkinson’s Disease (PD) Models
• Early vs. Late Intervention: Studies confirm that anle138b can mitigate motor deficits, neuronal loss, and protein aggregation in transgenic α-syn models. Notably, it retains some efficacy even when administration starts after symptom onset, although early treatment remains more effective.
• Dopaminergic Rescue: In newer rodent models featuring truncated α-synuclein (1–120 αSyn), anle138b reversed impaired striatal dopamine release and partially rescued dopaminergic neuron death, correlating with a reduction in the density of dense α-syn aggregates.
• Tauopathies
  Anle138b also reduces pathogenic tau aggregates in models of frontotemporal dementia/Alzheimer-type tau pathology (e.g., P301S tau mice). Treated animals show delayed disease progression, less neuroinflammation, and improved survival — reinforcing the compound’s apparent broad activity against protein oligomerization.
• Multiple System Atrophy (MSA)
• Combination Approaches: One study combined anle138b with an active immunotherapy (PD03 AFFITOPE®) targeting α-syn in oligodendroglial inclusions. The combination partially rescued nigrostriatal degeneration in an MSA model, implying that anle138b’s oligomer modulation can synergize with immunologic clearance strategies.
• Stage of Disease Matters: In advanced MSA models that already exhibit extensive neurodegeneration, anle138b provided only partial motor improvement, and did not halt cell loss or remove large insoluble aggregates. This underscores that efficacy can be limited in late-stage disease, supporting earlier intervention whenever possible.
• Prion Diseases
  Although prion models were not the primary focus of most new articles, additional data reaffirm that anle138b disrupts pathogenic protein aggregation in prion disease models, slowing progression and extending survival. This cross-disease activity suggests a shared structural vulnerability in misfolded oligomeric proteins that anle138b can exploit.

2.4 Results and State of Clinical Testing

• Preclinical Results: Published studies emphasize the compound’s strong potency in laboratory settings, including improved behavioral outcomes in animal models.
• Phase I Trials: As of now, early clinical investigations have been limited, and complete Phase I data (focusing on safety and dosing) have not yet been extensively reported.
• Future Prospects: For Anle138b to gain traction as a viable therapeutic, it needs thorough clinical evaluations, ideally progressing quickly toward Phase II and Phase III trials to ascertain efficacy in human patients.

3. Open Questions

Optimal Dosing and Delivery

• While animal models suggest various effective dosages, it remains unclear how best to deliver the compound in humans for maximal therapeutic benefit.

Long-Term Safety

• Potential side effects over longer periods remain unknown. Extended follow-up will be essential to determine whether Anle138b is safe for chronic use in Parkinson’s disease.

Biomarker Development

• Objective biomarkers are needed to measure the efficacy of anti-aggregation therapies. This could include imaging or molecular markers that reflect alpha-synuclein burden and neuronal health.

Combination Therapy

• Since neurodegenerative diseases often have multifaceted pathologies, exploring the synergy of Anle138b with immunotherapy, neuroprotective agents, or other disease-modifying treatments may be beneficial. Combining anle138b with targeted immunotherapy or other disease-modifying agents may amplify its benefits, as shown by synergistic effects on aggregate clearance and neuroprotection in MSA models. This multi-pronged approach might help overcome the compound’s limitations in later disease stages

4. Call for Action

Expand Research Efforts

• Encourage more laboratories and collaborations to replicate current findings, ensuring a broader research base and more robust data.

Accelerate Clinical Trials

• Prompt initiation of larger, multi-center clinical trials is crucial. If preliminary data continue to show promise, regulatory authorities should prioritize fast-tracking these studies.

Secure Funding and Partnerships

• Increased financial support and industry partnerships will help bring Anle138b into late-stage clinical development faster, potentially delivering a disease-modifying therapy to patients sooner.

Enhance Public Awareness

• Advocacy and patient organizations can help highlight the promise of Anle138b and encourage the research community to further investigate this compound’s potential.

Conclusion

Anle138b represents an intriguing candidate for disease-modifying therapy in Parkinson’s disease due to its anti-aggregation properties against alpha-synuclein.

While initial results from small research groups have been encouraging, it remains urgent to validate its efficacy and safety through larger, more rigorous clinical trials. While consistent improvements in protein aggregation markers, pathology, and function have been demonstrated, especially in earlier stages, the results in more advanced disease models highlight both the challenges and the promise of anle138b-based interventions.

With increased research efforts, collaboration, and adequate funding, Anle138b may pave the way for new treatments that slow or even halt the progression of Parkinson’s disease. The time to act is now — concerted efforts can accelerate the journey from bench to bedside

Key publications

1. Fellner, L., Kuzdas-Wood, D., Levin, J., Ryazanov, S., Leonov, A., Griesinger, C., Giese, A., Wenning, G. K., & Stefanova, N. (2016). Anle138b partly ameliorates motor deficits despite failure of neuroprotection in a model of advanced multiple system atrophy. Frontiers in Neuroscience, 10(99), 1–9.

2. Wagner, J., Ryazanov, S., Leonov, A., Levin, J., Shi, S., Schmidt, F., Prix, C., Pan-Montojo, F., Bertsch, U., Mitteregger-Kretzschmar, G., Geissen, M., Eiden, M., Leidel, F., Hirschberger, T., Deeg, A. A., Krauth, J. J., Zinth, W., Tavan, P., Pilger, J., Zweckstetter, M., Frank, T., Bähr, M., Weishaupt, J. H., Uhr, M., Urlaub, H., Teichmann, U., Samwer, M., Bötzel, K., Groschup, M., Kretzschmar, H., Griesinger, C., & Giese, A. (2013). Anle138b: A novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson’s disease. Acta Neuropathologica, 125(6), 795–813.

3. Levin, J., Schmidt, F., Boehm, C., Prix, C., Bötzel, K., Ryazanov, S., Leonov, A., Griesinger, C., & Giese, A. (2014). The oligomer modulator anle138b inhibits disease progression in a Parkinson mouse model even with treatment started after disease onset. Acta Neuropathologica, 127(5), 779–780.

4. Wagner, J., Krauss, S., Shi, S., Ryazanov, S., Steffen, J., Miklitz, C., Leonov, A., Kleinknecht, A., Göricke, B., Weishaupt, J. H., Weckbecker, D., Reiner, A. M., Zinth, W., Levin, J., Ehninger, D., Remy, S., Kretzschmar, H. A., Griesinger, C., Giese, A., & Fuhrmann, M. (2015). Reducing tau aggregates with anle138b delays disease progression in a mouse model of tauopathies. Acta Neuropathologica, 130(5), 619–631.

5. Wegrzynowicz, M., Bar-On, D., Calo’, L., Anichtchik, O., Iovino, M., Xia, J., Ryazanov, S., Leonov, A., Giese, A., Dalley, J. W., Griesinger, C., Ashery, U., & Spillantini, M. G. (2019). Depopulation of dense α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model. Acta Neuropathologica, 138(4), 575–595.

6. Kuebler, L., Buss, S., Leonov, A., Ryazanov, S., Schmidt, F., Maurer, A., Weckbecker, D., Landau, A. M., Lillethorup, T. P., Bleher, D., Saw, R. S., Pichler, B. J., Griesinger, C., Giese, A., & Herfert, K. (2021). [11C]MODAG-001 — towards a PET tracer targeting α-synuclein aggregates. European Journal of Nuclear Medicine and Molecular Imaging, 48(6), 1759–1772.

7. Lemos, M., Venezia, S., Refolo, V., Heras-Garvin, A., Schmidhuber, S., Giese, A., Leonov, A., Ryazanov, S., Griesinger, C., Galabova, G., Staffler, G., Wenning, G. K., & Stefanova, N. (2020). Targeting α-synuclein by PD03 AFFITOPE® and Anle138b rescues neurodegenerative pathology in a model of multiple system atrophy: clinical relevance. Translational Neurodegeneration, 9, 38.

8. Dervişoğlu, R., Antonschmidt, L., Nimerovsky, E., Sant, V., Kim, M., Ryazanov, S., Leonov, A., Fuentes-Monteverde, J. C., Wegstroth, M., Giller, K., Mathies, G., Giese, A., Becker, S., Griesinger, C., & Andreas, L. B. (2023). Anle138b interaction in α-synuclein aggregates by dynamic nuclear polarization NMR. Methods, 214, 18–27.