Biomedical Engineering Reference
In-Depth Information
cytokines. HIF-1a activates a cascade of proteins associated with blood vessel
formation. This comprehensive approach contrasts with angiogenic therapies
employing a single protein, such as a VEGF isoform, given as a gene or as a recom-
binant protein.
Genzyme's engineered version of HIF-1a turns on the expression of many
angiogenic proteins, including all known VEGF isoforms, angiopoietins 2 and 4,
and placenta growth factor among others; it may produce a more robust and longer-
lasting angiogenic effect than gene therapies based on a single growth factor.
HIF-1a has been shown in preclinical studies to turn on the expression of proteins
associated with the body's response to tissue ischemia, including many associated
with blood vessel formation.
Genzyme had conducted phase I clinical trials of HIF-1a gene therapy in
patients with critical limb ischemia (CLI). Investigators reported that Ad2/HIF-
1a/VP16 appears safe, with no treatment-related serious adverse events observed
in any of the patients treated, even at the highest dose. The strongest suggestion of
bioactivity was complete healing of leg ulcers. In addition, all treated patients who
experienced rest pain, but no ulcers at the start of the trial, had resolution of their
rest pain at 1 year. The limb survival rate for treated patients was 67% versus an
expected rate of 50-65% at 1 year. These improvements were observed despite
significant challenges posed by the advanced nature of the patients' disease, inves-
tigators said. All patients enrolled in the trial had extensive blockage of their blood
vessels prior to the trial, and many had previous bypass operations. Based on the
results seen in this trial, Genzyme started a randomized double-blind placebo con-
trolled phase II clinical trial of HIF-1a in 2005 in patients with intermittent claudi-
cation, a type of peripheral arterial disease that results in disabling pain or fatigue
in the legs, brought on by exercise. In addition to safety, the trial evaluated the
effectiveness of each dose in several measures of efficacy. The primary endpoint
was change in the maximum amount of time a patient can walk on a treadmill
without stopping due to claudication symptoms. Other endpoints include the
amount of time it takes while walking for the onset of claudication pain; change in
blood flow to the limbs, as measured using the ankle-brachial index; and various
quality of life assessments. The primary endpoint was evaluated at 6 months and
study participants were followed for 2 years. The trial is now listed as completed
and inactive with no publication of the results.
HGF Gene Therapy for Peripheral Arterial Disease
AnGes MG is developing DNA-based delivery of hepatocyte growth factor
(HGF), an angiogenic factor, for indications related to PAD and IHD. It is in phase
II trials in the USA and phase III trials in Japan for PAD. The DNA-based HGF
therapy, combined with Vical's nonviral gene delivery technology, can be deliv-
ered with a simple injection. This is intended to cause production of HGF locally
at the site of injection for an extended period. The resulting angiogenic effect
is expected to alleviate ischemic disease, in which narrowed or diseased blood
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