Enabling Novel Treatments for Nervous System Disorders by Improving Methods for Traversing the Blood–Brain Barrier Proceedings of a Workshop (2018) / Chapter Skim
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2 Traversing the BloodBrain Barrier: Challenges and Opportunities
2 Traversing the BloodBrain Barrier: Challenges and Opportunities
Pages 5-12
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From page 5... ...
Accelerated Approval Pathway, suggested Francesca Bosetti, program director for Stroke in the Neural Environment Cluster at the National Institute of Neurological Diseases and Stroke. In addition, individuals affected by rare serious diseases may be more motivated to participate in clinical trials.
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From page 6... ...
, multiple sclerosis, and chronic traumatic encephalopathy, as well as stroke and infectious diseases of the brain, such as those caused by the human immunodeficiency virus, said Zlokovic. He added that there are also rare monogenic neurological diseases associated with genetic defects in nonneuronal cells that cause disruption of the neurovascular unit and breakdown of the BBB (Zhao et al., 2015)
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From page 7... ...
Understanding the Complex Biology of the BBB The major reasons for the high attrition rates in CNS drugs include a limited understanding of drug permeability at the BBB, drug distribution in the brain, and target engagement in the brain, said Danica Stanimirovic. Understanding the BBB molecular makeup should enable identification of new targets for both managing disease and delivering drugs, she said.
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Creating Suitable Models for Understanding BBB Dysfunction Zlokovic commented that available methods in humans to study BBB dysfunction do not distinguish among the different mechanisms of permeability, for instance paracellular via transcytosis versus transcellular via breakdown of tight junctions. While animal models can distinguish among these mechanisms, they present other challenges, he said.
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From page 9... ...
Despite the limitations of animal models, they are essential to develop potential biomarkers and to gather strong efficacy data before undertaking expensive preclinical studies and even more expensive clinical studies, said Bosetti. Conducting Complex Preclinical Studies The preclinical evaluation of complex molecules capable of traversing the BBB is not simple, but it is necessary to understand the attributes that would enable them to be moved through the development process into clinical translation, said Stanimirovic.
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From page 10... ...
To accelerate translation, Stanimirovic also suggested a need to streamline regulatory pathways while managing toxicity, safety, and immunogenicity. Deepa Rao of FDA's Division of Psychiatry Products noted that this can be particularly challenging when therapeutics combine multiple components, such as a drug and device, two enzymes, or an antibody and enzyme.
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From page 11... ...
Developing and Refining Novel Approaches for Drug Delivery Innovation is now on the drug delivery side, said Pardridge. Proteins and polypeptides may now be delivered to the brain through a variety of approaches: • Trojan horse approaches using fusion molecules (Walsh)
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From page 12... ...
Bernd Stowasser, head of global public–private partnerships at Sanofi, and a core member of the European Federation of Pharmaceutical Industries and Associations (EFPIA) Innovative Medicines Strategy Priority Workgroup, added that collaborations such as public–private partnerships provide benefits for all stakeholders: academic researchers, industry, and patients.
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