Oral Protein Therapy for the Future –Transport of Glycolipid-Modified Proteins:Vision or Fiction?
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Abstract
The reliable and early diagnosis of common complex
multifactorial diseases depends on the individual determination of all
(or as many as possible) polymorphisms of each susceptibility gene
together with amount and type of the corresponding gene products and
their downstream effects, including the synthesis and flux of
metabolites and regulation of signalling processes. In addition, this
system’s biology-driven personalized diagnosis must be accompanied by
options for personalized reliable and early therapy. In the mid-term,
the direct substitution or inhibition of the proteins encoded by the
corresponding defective gene products of the susceptibility genes
exerting lower or higher activity by administration of the ‘normal’
proteins or inhibitory antibodies, respectively, seems to be most
promising. The critical hurdle of oral bioavailability as well as
transport into the cytoplasm of the target cells, if required, could be
overcome by therapeutic proteins with carboxy-terminal modification by
glycosylphosphatidylinositol (GPI). This may be deduced from recent
experiments with rat adipocytes. Here this membrane-anchoring glycolipid
structure induces the sequential transport of proteins from special
regions of the plasma membrane via the surface of intracellular lipid
droplets to special membrane vesicles, which are finally released from
the adipocytes together with the associated GPI proteins. It remains to
be studied whether similar molecular mechanisms operate in intestinal
epithelial cells and may enable the transport of GPI proteins from the
intestinal lumen into the blood stream. If so, modification of proteins
encoded by (combinations of) susceptibility genes with GPI could
significantly facilitate the personalized therapy of common diseases on
the basis of ‘inborn’ safety, efficacy, rapid realization and oral
application.
© 2010 S. Karger AG, Basel
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