http://scienceblogs.com/notrocketscience/2009/04/retrocyclins_a_defence_against_hiv_reawakened_after_7_millio.php

The original paper is available for anyone to read at http://biology.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pbio.1000095

What is interesting is that although they used antibiotics called aminoglycosides to restore production of this gene they mention a new drug named PTC-124 that works in the same way as the aminoglycosides. PTC-124 has the advantage of being far less toxic than the aminoglycosides when used over long periods of time, and is currently performing well in clinical trials for the genetic diseases Duchenne Muscular Dystrophy and Cystic Fibrosis. If these trials continue to go well and in vitro and animal studies of PTC-124 against HIV are promising than PTC-124 may soon be in trails against HIV.

This is another example of why studying the differences between species can lead to valuable discoveries, and of course animal research was very important to the development and evaluation of PTC-124 prior to the start of human clinical trials.

“Through in vitro characterization in translation
assays, we have demonstrated that PTC124 induces
dose- and time-dependent ribosomal readthrough of
premature stop codons with greater potency than
gentamicin. PTC124’s activity is selective; it does
not permit ribosomes to read through normal stop
codons in preclinical systems. In the same nonsense
mutation−containing mouse models of CF2
and DMD7 used to evaluate gentamicin, we have
shown that treatment with PTC124 promotes the production
of full-length, functional CFTR12 and dystrophin, respectively. The CFTR protein is able
to restore chloride channel activity and the dystrophin
is appropriately localized to muscle cell membranes
and is functionally active, reducing muscle
contraction injury and decreasing pathologic leakage
of creatine kinase from muscles into the systemic
circulation. Although precise exposure-response
correlations have not been established, the nonclinical
efficacy pharmacology data imply that achieving
relatively continuous plasma concentrations above a
target trough value of ~2 μg/mL may be associated
with discernable readthrough activity, whereas achieving
a trough value of ~10 μg/mL may be associated
with maximal effects.
In support of clinical development of PTC124, we
have performed comprehensive preclinical safety
testing. In safety pharmacology studies in rats and
dogs, we have demonstrated that oral administration
of PTC124 induces no adverse neurological, pulmonary,
or cardiovascular effects at doses through
1500 mg/kg. In toxicology studies in rats and dogs at
oral doses through 1500 mg/kg for 28 days, PTC124
has shown good tolerability. In these studies, toxicokinetic
exposure levels substantially exceeded the target
concentrations required for nonsense suppression
in preclinical efficacy pharmacology studies. We have
also documented that PTC124 demonstrates virtually
no human ether-à-go-go-related gene (hERG) channel
inhibition, has no discernable antibiotic activity
against gram-positive or gram-negative organisms,
and is not mutagenic or genotoxic in standard in vitro
and in vivo assays. PTC124 is stable when incubated
with human liver microsomes.
Based on the available preclinical data, we are
developing PTC124 as a therapy for patients with
nonsense mutation–mediated CF and DMD.”

Hirawat S. et al. “Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers.” J Clin Pharmacol. Volume 47(4), pages 430-444 (2007) DOI:10.1177/0091270006297140