Abstract
Despite the enormity of the societal and health burdens caused by Alzheimer’s disease (AD), there have been no FDA approvals for new therapeutics for AD since 2003. This profound lack of progress in treatment of AD is due to dual problems, both related to the blood–brain barrier (BBB). First, 98% of small molecule drugs do not cross the BBB, and ~100% of biologic drugs do not cross the BBB, so BBB drug delivery technology is needed in AD drug development. Second, the pharmaceutical industry has not developed BBB drug delivery technology, which would enable industry to invent new therapeutics for AD that actually penetrate into brain parenchyma from blood. In 2020, less than 1% of all AD drug development projects use a BBB drug delivery technology. The pathogenesis of AD involves chronic neuro-inflammation, the progressive deposition of insoluble amyloid-beta or tau aggregates, and neural degeneration. New drugs that both attack these multiple sites in AD, and that have been coupled with BBB drug delivery technology, can lead to new and effective treatments of this serious disorder.
Highlights
There has been a striking failure in global drug development for Alzheimer’s Disease (AD), as there has not been a new drug approved for AD since 2003 [6]
While the difficulty in finding new treatments that yield positive clinical trials in AD is indisputable, the history of AD drug development is inexplicable in the context of the blood–brain barrier
Given that 98% of all small molecule drugs, and ~100% of all biologics, do not cross the blood–brain barrier (BBB) [7], how could it be that the BBB is systematically ignored in AD drug development? A 2020 EU/US Clinical Trials for Alzheimer’s Disease (CTAD) Task Force reviews current AD drug development and never mentions the BBB [145]
Summary
Alzheimer’s Disease (AD) afflicts over 50 million people world-wide, and this health burden costs over 1% of global GDP [1]. Searching Pubmed for ‘Alzheimer’s disease drug development and blood–brain barrier drug delivery’ lists 191 citations, or 1.9% Over half of these citations pertain to nanoparticles, which have proven difficult to translate to human neurotherapeutics, so that >99% of all AD drug development projects are conducted in the absence of BBB drug delivery technology. One of the causes of the lack of development of BBB drug delivery technology within the pharmaceutical industry is the wealth of “BBB avoidance strategies.” These approaches to brain drug delivery are reviewed below, and lead the CNS drug developer into clinical trials of drugs that do not penetrate the brain, ending in a failed clinical trial. The re-engineering of biologics as BBB-penetrating IgG fusion proteins are reviewed in the context of a combination treatment plan for AD that attacks the disease at multiple levels, including neuro-inflammation, depletion of Abeta or Tau aggregates, and repair of dystrophic neurites
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