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Do We Need Anti-Prion Compounds to Treat Alzheimer's Disease?
Dieter Willbold1,2, Janine Kutzsche3
1Institute of Complex Systems, Structural Biochemistry (ICS-6), Forschungszentrum Jülich, 52425 Jülich, Germany. d.willbold@fz-juelich.de.
Background:
While phase III clinical trials for the treatment of Alzheimer's disease (AD) keep failing regardless of the target, more and more data suggest that the toxic protein assemblies of amyloid-beta protein (Aβ) and tubulin binding protein (TAU) behave like prions. Irrespective of the question of whether AD is theoretically or practically contagious, the presence of a self-replicating toxic etiologic agent in the brains of AD patients must have decisive consequences for drug development programs and clinical trial designs.
Objectives:
We intend to challenge the hypothesis that the underlying etiologic agent of AD is behaving prion-like. We want to discuss whether the outcome of clinical trials could have been predicted based on this hypothesis, and whether compounds that directly disassemble the toxic prion could be more beneficial for AD treatment.
Method:
We collected publicly accessible pre-clinical efficacy data of Aβ targeting compounds that failed or still are in phase III clinical trials. We describe the desired properties of an anti-prion compound and compare it the properties of past and current phase III drug candidates.
Results:
We could not find convincing and reproducible pre-clinical efficacy data of past and current phase III drug candidates on cognition other than in preventive treatment settings. The desired properties of an anti-Aβ-prionic compound are fulfilled by the drug candidate RD2, which has been developed to directly disassemble toxic Aβ oligomers.
Conclusion:
RD2 is the first anti-prion drug candidate. It is able to enhance cognition and impede neurodegeneration in three different transgenic AD mouse models, even under truly non-preventive conditions and even when applied orally. In addition, it is safe in humans.
Insights
Alzheimer's disease (AD) pathology may involve prion-like proteins. A new drug candidate, RD2, shows promise in disassembling toxic protein clumps and improving cognition in AD mouse models, even when given orally and safely in humans.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Alzheimer's disease (AD) clinical trials frequently fail, despite targeting amyloid-beta (Aβ) and tau proteins.
- Emerging evidence suggests Aβ and tau assemblies in AD may act as prions, self-replicating toxic agents.
- This prion-like behavior has significant implications for AD drug development and clinical trial design.
Purpose of the Study:
- To evaluate the prion-like hypothesis for AD's underlying cause.
- To determine if this hypothesis could predict clinical trial outcomes.
- To explore the potential of compounds that directly disassemble toxic prions for AD treatment.
Main Methods:
- Analysis of pre-clinical efficacy data for Aβ-targeting compounds in failed or ongoing Phase III AD trials.
- Characterization of essential properties for an effective anti-prion compound.
- Comparison of these properties with existing and developmental AD drug candidates.
Main Results:
- Limited convincing pre-clinical efficacy data for cognition improvement was found for current AD drug candidates, except in preventive settings.
- The drug candidate RD2, designed to disassemble toxic Aβ oligomers, possesses the desired properties of an anti-Aβ-prionic compound.
- RD2 demonstrated efficacy in enhancing cognition and reducing neurodegeneration in three transgenic AD mouse models.
Conclusions:
- RD2 represents the first anti-prion drug candidate for Alzheimer's disease.
- It shows efficacy in improving cognition and impeding neurodegeneration in AD mouse models under non-preventive conditions.
- RD2 is safe for human use and can be administered orally.