Abstract
Alzheimer’s disease (AD) and treatment of the brain in aging require the development of new biologic drugs, such as recombinant proteins or gene therapies. Biologics are large molecule therapeutics that do not cross the blood-brain barrier (BBB). BBB drug delivery is the limiting factor in the future development of new therapeutics for the brain. The delivery of recombinant protein or gene medicines to the brain is a binary process: either the brain drug developer re-engineers the biologic with BBB drug delivery technology, or goes forward with brain drug development in the absence of a BBB delivery platform. The presence of BBB delivery technology allows for engineering the therapeutic to enable entry into the brain across the BBB from blood. Brain drug development may still take place in the absence of BBB delivery technology, but with a reliance on approaches that have rarely led to FDA approval, e.g., CSF injection, stem cells, small molecules, and others. CSF injection of drug is the most widely practiced approach to brain delivery that bypasses the BBB. However, drug injection into the CSF results in limited drug penetration to the brain parenchyma, owing to the rapid export of CSF from the brain to blood. A CSF injection of a drug is equivalent to a slow intravenous (IV) infusion of the pharmaceutical. Given the profound effect the existence of the BBB has on brain drug development, future drug or gene development for the brain will be accelerated by future advances in BBB delivery technology in parallel with new drug discovery.
Highlights
Progress in the development of new pharmaceuticals for the treatment of the brain in aging, including Alzheimer’s disease (AD), has been slow because the products of biotechnology, recombinant proteins or gene therapies, are all large molecule pharmaceuticals that do not cross the blood-brain barrier (BBB)
A fusion protein of a mouse-specific TfRMAb and the human TNFR2 extracellular domain (ECD), which forms the active site of etanercept, was engineered and shown to retain high-affinity binding both for the mouse TfR1, to enable BBB transport, and chronic administration of the TfRMAb-TNFR fusion protein to double transgenic AD mice caused a reduction in Abeta amyloid plaque, a reduction in markers of neuroinflammation, and improved recognition memory (Chang R. et al, 2017)
Chronic administration of the TfRMAb-EPO fusion protein to double transgenic AD mice resulted in a reversal of synaptic loss and an improvement in spatial memory (Chang et al, 2018). These results show that multiple biologics that intervene at different sites within the disease cascade of AD can be developed as future therapeutics for AD, providing the biologic is re-engineered for BBB transport
Summary
Progress in the development of new pharmaceuticals for the treatment of the brain in aging, including Alzheimer’s disease (AD), has been slow because the products of biotechnology, recombinant proteins or gene therapies, are all large molecule pharmaceuticals that do not cross the blood-brain barrier (BBB). This is the first FDA approved biologic for a brain disease that crosses the BBB The development of this new treatment for SMA did not arise from a rational drug delivery platform, but rather was a product of the serendipitous finding that the AAV9 serotype traverses the BBB (Foust et al, 2009). The amyloid plaque of AD can be reduced by AAAs following direct intracerebral injection of the antibody (Solomon et al, 1997) In these early studies, the AAA was injected directly into the brain, because the FIGURE 1 | Model for combination therapy of Alzheimer’s disease (AD) with blood-brain barrier (BBB)-penetrating biologic drugs is based on blocking the pathway leading to dementia at multiple levels within the brain. Prior to the discussion of transvascular drug delivery to the brain, it is necessary to review intra-thecal drug delivery to the brain, since this has been the default approach to brain drug delivery for decades
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