Biomedical Engineering Reference
In-Depth Information
TABLE 26.2 Substances in Clinical Trials
Name
CPP and Cargo
Targeted Disease
Phase
References
KAI-9803
TAT-PKC
d
Myocardial infarction and
cerebral ischemia
Phase IIb
[115,122,123]
RT001
A lysine rich domain in between two
TAT— botulinum toxin type A
Wrinkles
Excessive sweating
Phase IIb
Phase I
[124]
AVI-5126
[(R-AHx-R)4]—NEUGENE antisense
Cardiovascular retenosis and
cardiovascular disease
Phase II
[125]
YARA
a
-phosphorylated HSP20
AZX100
Dermal scarring
Phase II
[118,119,126]
AM-111
TAT-c-Jun N-terminal kinase (JNK)
inhibitors
Hearing loss
Phase IIb
[127-129]
XG-102
TAT-c-Jun N-terminal kinase (JNK)
inhibitors
Stroke
Phase I
[130-132]
PSORBAN
1
Polyarginine (R8)-CsA
Psoriasis
Phase II discontinued
[117]
p28
b
forms a complex with p53
inside the cell
P28
Advanced cancer
Phase I
[122]
[107]
DTS-108
Vectocell- SN38 a topoisomerase I
inhibitor
Colorectal cancers
Phase I
[108,133]
POP33
PTD-ODD-caspase-3
Pancreatic cancer
Will start clinical
studies shortly
[111]
CPP-DRBD-siRNA
Leukaemia and glioblastoma but
attractive for several diseases
Preclinical
[112]
Truncated TAT-p53
Cancer
Will start clinical
studies shortly
[113]
AVI-5038
(RXRRBR)2 - PMO
Duchenne muscular dystrophy
Aborted just before
clinical studies
[120,121,125]
a
YARA has the amino acid sequence YARAAARQARA.
b
p28 is a CPP derived from the protein azurin excreted by Pseudomonas aeruginosa.
survival in hypoxic environment and is in turn degraded by
oxygen-dependent degradation (ODD). Control of HIF-1
a
is of interest for the treatment of cancers. TAT-ODD-cas-
pase-3 fusion protein, abbreviated TOP3, was shown to
reduced tumor masses when injected into tumor bearing
mice and specifically targeted hypoxic cells that were HIF-
1
a
active but experienced no effect on normoxic cells
[109,110]. The combination of both TOP3 and irradiation
gave a significant long-term suppression of tumor growth
[110]. Efforts to find a new CPP with an even higher
transduction activity than TAT resulted in a prodrug called
POP33. POP33 has displayed effective anticancer propert-
ies, suppressing malignant progression of pancreatic tumor
cells in animal models by selectively inducing apoptosis via
increase of caspase 3 activity [111]. Clinical studies are
reported to start shortly. Short interfering RNA, siRNA, have
been shown to have a gene silencing effect but the clinical
use have been limited due to poor internalization. A new
technology to deliver siRNA has been presented by Traversa
therapeutics by fusing it to a double stranded RNA-binding
domain fused with multiple CPPs, and preclinical studies are
currently performed [112].
Justensen et al. (2007) presents another therapeutic
method for the treatment of cancer. Here a 11 amino acid
sequence of the TAT peptide is fused to the tumor suppressor
protein p53 with the intention to treat cancer [113]. The
preclinical studies have shown promising results and clinical
studies are reported to start shortly.
CPPs have shown encouraging protective effects in dif-
ferent ischemia models for both neuroprotection and car-
dioprotection, which has been an unmet therapeutic need.
Cardiovascular protective effects due to an inactivation of
protein kinase C, PKC, have been seen in animal models
[114]. KAI pharmaceuticals have a substance named KAI-
9803, which is a TAT-conjugate with protein kinase C
d
peptide inhibitor developed for the treatment of acute myo-
cardial infarction [115]. KAI-9803 significantly reduced
infarct size and the protection ability against reperfusion
injury was maintained for up to 1week after intravenous
injection (kaipharma.com).
Using inhibitors for c-Jun N-terminal kinase (JNK),
which is responsible for stress stimuli and involved in
apoptosis, Xigen and Auris Medical have collaborated
and present two different compounds, named XG-102 and
AM-111, in clinical studies for the treatment of stroke and
hearing loss, respectively.
AVI-5126 is a polyarginine and aminohexanoic-based
CPP developed by AVI Biopharma that targets the c-myc
gene. This antisense technology is currently in a Phase II
clinical trial for treatment of cardiovascular diseases.
Search WWH ::
Custom Search