Biomedical Engineering Reference
In-Depth Information
Foxp3, HHph-1-Foxp3, fusion protein inhibited cytokine
production and T-cell activation that resulted in less tissue
inflammation in an animal model after both local and
systemic administration [16]. The fusion protein seemed
to be specific for T-cell functions and biological effect was
seen 4 days after the termination of treatment [16]. One
possible therapeutic approach for diabetes is transplantation
by viable islet cells. There are several limitations such as
several steps of organ procurement, loss of surviving signals,
and limitations of nutrients and oxygen that affect the
transplantable islet viability and yield [99]. Using two
anti-apoptotic proteins fused to TAT, namely TAT-BH4
and TAT-Bcl-xl, protected islets from staurosporine-induced
apoptosis [99]. Treatment of islets with either TAT-HA or
TAT-Bcl-xl fusion proteins showed 20-40% less dead cells,
respectively, after 48 h compared to controls [99]. Diabetes
needs to be carefully monitored and the lifelong treatment of
injections and/or diet.
One of the major causes of hepatocellular carcinoma,
cirrhosis, and chronic hepatitis is infection by the hepatitis B
virus (HBV) [100]. In chronic HBV infection, the HBV
nucleocapsid or core antigen, called HBcAg, is the only
antigen that generates a prominent immune response
[100,101]. There is a distinct difference in HBcAg-specific
immune response between the patients with chronic HBV
and the patient that can clear the virus. The specific response
from cytotoxic T cells to HBcAg was strongly reduced or
even below detection in patients with chronic HBV [100].
HBcAg-TAT fusion protein could effectively penetrate den-
dric cells and induce HBcAg-specific cytotoxic T lympho-
cytes in animal models [100]. A HBV core protein fused to
VP22 together with a dominant negative mutant signifi-
cantly inhibited the HBV replication [102].
The anti-apoptotic protein Bcl-xl fused to TAT was
effectively transduced into neurons when intraocularly
injected in animal models [61]. The survival rate of retinal
ganglion cells was two times higher in TAT-Bcl-xl treated
mice compared to control 14 days postsurgery [61]. Intra-
venous administration after ischemic insult resulted in an
efficacious transduction of the brain tissue and reduced brain
injury in vivo [103]. TAT-Bcl-xl effect on postischemia was
examined in animal models where induction of cerebral
ischemia was performed followed by intravenous injection
of fusion protein [45]. Behavioral studies using the rota
rod, water maze, and tight rope test were performed and the
TAT-Bc l -x l t r ea t ed mi ce . At day 4 after the induced
ischemia, the mice were sacrificed and the extent of
brain injury was assessed using terminal deoxynucleotidyl
transferase dUTP nick end labeling (TUNEL) and infarct
size analysis. The effects of TAT-Bcl-xl on hippocampal
endogenous neurogenesis were examined after induced
ischemia in mice [63]. TAT-Bcl-xl treated mice had
increased survival of ischemia-induced newborn immature
and mature neuronal cells.
Another protein of interest for treatment of ischemic
injury is glial cell-derived neurotrophic factor (GDNF),
which promotes neuronal survival. TAT-GDNF fusion pro-
tein was reported to significantly reduce brain injury when
administered intravenously after ischemic insult in animal
models [103].
Nogo-A extracellular peptide residue (NEP1-40) pro-
motes axonal regrowth and recovery after CNS injury but
the use is limited by the inability to cross the blood-brain
barrier [104]. Importantly, TAT-NEP1-40 fusion protein is
able to cross the blood-brain barrier and inhibit neuronal
apoptosis after induced ischemia in animal models [104].
One therapeutic approach to treat osteoporosis is by
inhibiting the NF-
k
B proteins that are involved in chronic
inflammatory diseases and essential for osteoclast formation
by the I
k
B
a
protein [47,60,98]. The TAT-fused I
k
B
a
protein
efficiently entered osteoclasts and blocked bone resorption
in a nontoxic fashion [60]. TAT fused to a protein such as
calcineurin A
a
or a small peptide such as hemagglutinin
gave a very quick transduction into both osteoclasts and
osteoblasts in primary cell culture and activity could even be
detected for up to 5 days, which could be a therapeutic
approach for treating osteoporosis [20]. The TAT-calci-
neurin A
a
fusion protein was active and regulated osteoblast
differentiation and maintaining of the protein levels could be
seen in 50% of the cells up to 5 days after a single
administration [20].
Antibodies have been reported to efficiently and specifi-
cally internalize cells through a TAT fusion protein in a
nontoxic manner [105]. The use of CPP linked to antibodies
for intracellular targets have a limited half-life and do not
cause any permanent genetic alteration which otherwise was
the major concern of recombinant DNA technology for
clinical purposes and detection [106].
26.4.2 CPPs Used in Clinical Trials
The therapeutic interest in CPPs has so far resulted in a few
clinical trials, which are summarized in the Table 26.2.
Several therapeutics against cancer used CPP as trans-
duction technique. P28 is a novel CPP, developed by CDG
therapeutics, from the protein azurin excreted by Pseudom-
onas aeruginosa [107]. P28 forms an intracellular complex
with the tumor suppressor protein p53, which inhibits
proliferation and induce apoptosis and it is tested with the
intention to treat solid tumors, currently in a phase I study.
SN38 is an effective topoisomerase I inhibitor proven to
be efficient antitumor agent, but the low solubility limits the
clinical use [108]. DTS-108 is a water-soluble version of the
parent drug SN38 linked to a highly charged Vectocell
peptide [108]. DTS-108 has shown to have lower toxicity
in preclinical animal studies.
Cancer cells can differentiate in hypoxic environment.
The hypoxia inducible factor (HIF) contributes to cell
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