Anti-HIV agent as a Vaccine

Anti-HIV agent as a Vaccine

 In a remarkable new advance against the virus that causes AIDS, scientists from the Jupiter, Florida campus of The Scripps Research Institute (TSRI) has announced the creation of a novel drug candidate that is so potent and universally effective, it might work as part of an unconventional vaccine.

The research, which involved scientists from more than a dozen research institutions, was published February 18 online ahead of print by the journal Nature.

The study shows that the new drug candidate blocks every strain of HIV-1, HIV-2 and SIV (simian immunodeficiency virus) that has been isolated from humans or rhesus macaques, including the hard-to-stop variants. It also protects against much-higher doses of virus than occur in most human transmission and does so for at least eight months after injection.

"Our compound is the broadest and most potent entry inhibitor described so far," said Michael Farzan, a TSRI professor who led the effort. "Unlike antibodies, which fail to neutralize a large fraction of HIV-1 strains, our protein has been effective against all strains tested, raising the possibility it could offer an effective HIV vaccine alternative."

Figure Showing electron micrograph of HIV particles infecting a human T-cell

Blocking a Second Site

When HIV infects a cell, it targets the CD4 lymphocyte, an integral part of the body's immune system. HIV fuses with the cell and inserts its own genetic material -- in this case, single-stranded RNA -- and transforms the host cell into a HIV manufacturing site.

The new study builds on previous discoveries by the Farzan laboratory, which show that a co-receptor called CCR5 contains unusual modifications in its critical HIV-binding region, and that proteins based on this region can be used to prevent infection.

With this knowledge, Farzan and his team developed the new drug candidate so that it binds to two sites on the surface of the virus simultaneously, preventing entry of HIV into the host cell.

"When antibodies try to mimic the receptor, they touch a lot of other parts of the viral envelope that HIV can change with ease," said TSRI Research Associate Matthew Gardner, the first author of the study with Lisa M. Kattenhorn of Harvard Medical School. "We've developed a direct mimic of the receptors without providing many avenues that the virus can use to escape, so we catch every virus thus far."

The team also leveraged preexisting technology in designing a delivery vehicle -- an engineered adeno-associated virus, a small, relatively innocuous virus that causes no disease. Once injected into muscle tissue, like HIV itself, the vehicle turns those cells into "factories" that could produce enough of the new protective protein to last for years, perhaps decades, Farzan said.

Data from the new study showed the drug candidate binds to the envelope of HIV-1 more potently than the best broadly neutralizing antibodies against the virus. Also, when macaque models were inoculated with the drug candidate, they were protected from multiple challenges by SIV.

"This is the culmination of more than a decade's worth of work on the biochemistry of how HIV enters cells," Farzan said. "When we did our original work on CCR5, people thought it was interesting, but no one saw the therapeutic potential. That potential is starting to be realized."

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Bioinformatics Depatment

Parkinson’s disease: a dose-finding study

Parkinson’s disease: a dose-finding study

In advanced stages of Parkinson’s disease, serotonergic terminals take up L-DOPA and convert it to dopamine. Abnormally released dopamine may participate in the development of L-DOPA-induced dyskinesias. Simultaneous activation of 5-HT1A and 5-HT1B receptors effectively blocks L-DOPA-induced dyskinesias in animal models of dopamine depletion, justifying a clinical study with eltoprazine, a 5-HT1A/B receptor agonist, against L-DOPA-induced dyskinesias in patients with Parkinson’s disease. A double-blind, randomized, placebo-controlled and dose-finding phase I/IIa study was conducted. Single oral treatment with placebo or eltoprazine, at 2.5, 5 and 7.5 mg, was tested in combination with a suprathreshold dose of L-DOPA (Sinemet®) in 22 patients with Parkinson’s disease (16 male/six female; 66.6 ± 8.8 years old) with L-DOPA-induced dyskinesias. 

Figure: Brain Regions Affected by PD

Figure: PD Treatment Steps

A Wilcoxon Signed Rank Test was used to compare each eltoprazine dose level to paired randomized, placebo on the prespecified primary efficacy variables; area under the curve scores on Clinical Dyskinesia Rating Scale for 3 h post-dose and the maximum change of Unified Parkinson’s Disease Rating Scale part III for 3 h post-dose. Secondary objectives included effects on maximum Clinical Dyskinesia Rating Scale score, area under the curve of Rush Dyskinesia Rating Scale score for 3 h post-dose, mood parameters measured by Hospital Anxiety, Depression Scale and Montgomery Asberg Depression Rating Scale along with the pharmacokinetics, safety and tolerability profile of eltoprazine. A mixed model repeated measures was used for post hoc analyses of the area under the curve and peak Clinical Dyskinesia Rating Scale scores. It was found that serum concentrations of eltoprazine increased in a dose-proportional manner. Following levodopa challenge, 5 mg eltoprazine caused a significant reduction of L-DOPA-induced dyskinesias on area under the curves of Clinical Dyskinesia Rating Scale [–1.02(1.49); P = 0.004] and Rush Dyskinesia Rating Scale [–0.15(0.23); P = 0.003]; and maximum Clinical Dyskinesia Rating Scale score [–1.14(1.59); P = 0.005]. 

The post hoc analysis confirmed these results and also showed an antidyskinetic effect of 7.5 mg eltoprazine. Unified Parkinson’s Disease Rating Scale part III scores did not differ between the placebo and eltoprazine treatments. The most frequent adverse effects after eltoprazine were nausea and dizziness. It can be concluded that a single dose, oral treatment with eltoprazine has beneficial antidyskinetic effects without altering normal motor responses to L-DOPA. All doses of eltoprazine were well tolerated, with no major adverse effects. Eltoprazine has a favourable risk-benefit and pharmacokinetic profile in patients with Parkinson’s disease. The data support further clinical studies with chronic oral eltoprazine to treat L-DOPA-induced-dyskinesias.

Posted By:-

Bioinformatics Department