Oral Protein Therapy for the Future - Transport of Glycolipid-Modified Proteins: Vision or Fiction?

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
midterm, 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. Copyright (C) 2010 S. Karger AG, Basel