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Challenges and Promises in the Development of Neurotrophic Factor-Based Therapies for Parkinson’s Disease

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Abstract

Parkinson’s disease (PD) is a chronic movement disorder typically coupled to progressive degeneration of dopaminergic neurons in the substantia nigra (SN). The treatments currently available are satisfactory for symptomatic management, but the efficacy tends to decrease as neuronal loss progresses. Neurotrophic factors (NTFs) are endogenous proteins known to promote neuronal survival, even in degenerating states. Therefore, the use of these factors is regarded as a possible therapeutic approach, which would aim to prevent PD or to even restore homeostasis in neurodegenerative disorders. Intriguingly, although favorable results in in vitro and in vivo models of the disease were attained, clinical trials using these molecules have failed to demonstrate a clear therapeutic benefit. Therefore, the development of animal models that more closely reproduce the mechanisms known to underlie PD-related neurodegeneration would be a major step towards improving the capacity to predict the clinical usefulness of a given NTF-based approach in the experimental setting. Moreover, some adjustments to the design of clinical trials ought to be considered, which include recruiting patients in the initial stages of the disease, improving the efficacy of the delivery methods, and combining synergetic NTFs or adding NTF-boosting drugs to the already available pharmacological approaches. Despite the drawbacks on the road to the use of NTFs as pharmacological tools for PD, very relevant achievements have been reached. In this article, we review the current status of the potential relevance of NTFs for treating PD, taking into consideration experimental evidence, human observational studies, and data from clinical trials.

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Acknowledgments

Tiago Martins Rodrigues, André Jerónimo-Santos, Tiago Fleming Outeiro, Ana Maria Sebastião and Maria José Diógenes do not have any financial interest in this manuscript nor any potential conflicts of interest are foreseen. This work was supported by a Fundação para a Ciência e a Tecnologia (FCT) project grant. André Jerónimo-Santos is supported by an FCT fellowship grant (SFRH/BD/62828/2009) and Tiago Fleming Outeiro is supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain.

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  1. Instituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

    Tiago Martins Rodrigues, André Jerónimo-Santos, Ana Maria Sebastião & Maria José Diógenes

  2. Unidade de Neurociências, Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal

    Tiago Martins Rodrigues, André Jerónimo-Santos, Ana Maria Sebastião & Maria José Diógenes

  3. Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Goettingen, Goettingen, Germany

    Tiago Fleming Outeiro

  4. Unidade de Neurociências Celular e Molecular, Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal

    Tiago Fleming Outeiro

  5. Instituto de Fisiologia, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal

    Tiago Fleming Outeiro

  6. Unit of Neurosciences, Institute of Molecular Medicine, University of Lisbon, Portugal, Avenida Professor Egas Moniz, 1649-028, Lisbon, Portugal

    Maria José Diógenes

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  1. Tiago Martins Rodrigues
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Correspondence to Maria José Diógenes.

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T. M. Rodriques and A. Jerónimo-Santos contributed equally to this article.

Box 1. Future perspectives for neurotrophic factor-based strategies

Box 1. Future perspectives for neurotrophic factor-based strategies

  • New animal models that more closely reproduce Parkinson’s disease (PD) neurodegenerative process are needed.

  • The development of strategies that enhance neurotrophic factor (NTF) intraparenchymal perfusion—namely through the modulation of NTF interaction with proteins of the extracellular matrix.

  • Clinical trials that would recruit PD patients in the initial stage of the disease (which requires the development of appropriate biomarkers).

  • Clinical trials increased in their duration, with extended cohorts and improved in their design (e.g. the delayed-start design) as to enhance their sensibility to detect effects.

  • Data from individual patients in trials should not be overlooked as it could provide new insights, given the reported inter-individual variability in therapeutic response.

  • The delivery methods must be optimized.

  • The new methods of delivery must be translated into clinical practice (e.g. microspheres and ex vivo gene therapy using encapsulated cells).

  • Uncharted hypothesis ought to be tested in clinical trials (e.g. combinations of synergistic NTFs and the addition of NTFs to current therapies).

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Rodrigues, T.M., Jerónimo-Santos, A., Outeiro, T.F. et al. Challenges and Promises in the Development of Neurotrophic Factor-Based Therapies for Parkinson’s Disease. Drugs Aging 31, 239–261 (2014). https://doi.org/10.1007/s40266-014-0160-x

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