Therapeutic Strategies Involving MP

Therapeutic MP/Exosomes Crossing the Blood-Brain Barrier (BBB)

Properties of MP which govern their ability to cross the BBB are important for three reasons:

  • (i) Design or selection of MP for purposes of delivering drug therapy
  • (ii) For use as vectors of gene therapy
  • (iii) For insight on pathological aspects of certain MP types

Our readings indicate growing interest in using cell-derived MP/exosomes as vectors for gene therapy, avoiding risks of virus vectors. In reviewing literature on MP crossing the BBB, we identified at least five variables which appear to govern this capability:

  • 1. The presence of specific promoters of endocytosis. An example was cited in section “Heat Shock Proteins”: surface expression of ERK1/2, also called HSP27 [70].
  • 2. The presence of agent tending to disrupt endothelial integrity, increasing vascular permeability, for example, semaphorin3A [126] and the Nef protein of HIV [127].
  • 3. Pre-existing partial compromise of the BBB, such as by traumatic brain injury (TBI), facilitating crossing [128]. This may pertain to increased risk of neurodegenerative disorders in subjects with history of TBI and to the life-threatening “coagulopathy of trauma” which is prevalent in TBI [129].
  • 4. Electric charge (zeta potential) on MP is another determinant of passage across the BBB [130].
  • 5. Smaller size also favors passage, other factors being equal, as shown for nonbiological MP engineered for drug delivery [131, 132].

Much promising work in this direction is ongoing. Haney et al. developed exo- somes for delivery of catalase to PD patients [133]. Sampey et al. discuss the effect of viral infections on exosomes and suggest that viral mechanisms of crossing the

BBB might be engineered into exosomes [134]. de Rivero showed that neuron- derived exosomes delivered cargo of siRNA across the BBB of spine-injured animals [83]. Work of L. Alvarez et al. on exosomal delivery of siRNA to the mouse brain is often cited as pioneering [135]. Related work by Frolich et al. was earlier cited [49].

 
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