By David N. Leff
Editor's note: Science Scan is a roundup of recently published, biotechnology-relevant research.
The current multidrug anti-AIDS regimen called HAART - highly active anti-retroviral therapy - does reduce symptoms and death in HIV-infected individuals. While the triple-drug therapy may have pummeled the virus into a corner of the ring, HIV isn't down for the count. The ever-looming threat of drug resistance can get it back on its feet. Also, the expense and awkwardness of the medication limits the regimen's effectiveness. Instead of letting down their guard, virologists and clinicians remain in the market for new and better therapeutic compounds and strategies that target HIV replication.
One such innovative drug scored its first punch in a Phase I clinical trial as reported last month in the July 2000 Journal of Infectious Diseases. The article's title: "Single-dose safety, pharmacology and antiviral activity of the human immunodeficiency virus (HIV) type I entry inhibitor PRO 542 in HIV-infected adults."
PRO 542 is a recombinant antibody-like fusion protein that incorporates the HIV-binding region of the human cell-surface CD4 receptor into a human antibody-like molecule, and prevents the virus from breaking into its target cells. It was developed by Progenics Pharmaceuticals Inc., of Tarrytown, N.Y. This Phase I clinical trial of the drug aimed, by definition, at testing only safety, tolerance, dosage and immunogenicity. However, seven HIV-infected adults on HAART medication, and eight receiving no prior treatment, experienced significantly lowered levels of viremia - infectious virus load in their blood - a recognized endpoint for anti-retroviral therapies.
"There is an urgent need for new anti-retroviral therapies like PRO 542 that target novel stages of the HIV life cycle," observed clinician Jeffrey Jacobson, the paper's senior author. He is director of the AIDS Clinic at Mt. Sinai Medical Center in New York. "The favorable safety, pharmacologic and virologic outcomes of this trial," Jacobson added, "provide a compelling rationale for further clinical exploration of this novel agent."
That further exploration took the form of a multidose trial of PRO 542 in six HIV-infected children, announced by the company July 12th at the 13th World AIDS Conference in Durban, South Africa. All six showed decreases in HIV RNA, and three of them had lowered viremia, which persisted for up to two weeks following treatment.
Also at the AIDS Conference, Trimeris Inc., of Durham, N.C., reported positive clinical results of its HIV cell-fusion inhibitor, T-20, administered in combination with approved anti-retroviral drugs. PRO 542 and T-20 have shown in vitro synergy.
Brain's Least-Forgiving Tumor Type Plea Bargains With Antigenic Plus Cytotoxic Therapy - In Mice
In any unpopularity contest for the most incurable form of brain cancer, the crown would surely go to glioblastoma. Life expectancy after diagnosis averages 12 months. Surgery to trim down the tumor masses, followed by radiation and chemotherapy, aims to prolong life but not to attempt a cure. Because glioblastomas are so aggressively invasive and fast growing, at multiple tumor sites, they need a copious and expanding blood supply. This calls for angiogenesis - propagating a network of blood vessels to nourish the malignancies with oxygen and nutrients.
Urokinase (uPA), a plasminogen activator, is an enzyme intimately involved in tumor angiogenesis. Molecular geneticists at the Ludwig Institute for Cancer Research Branch in San Diego have identified an epitope - an antigenic peptide - from within uPA's sequence that controls the motility and contractility of the endothelial cells that line the tubular walls of blood vessels. They derived a peptide named E6 that inhibited tumor cell invasion in vitro, and showed anti-angiogenic and antitumor activity.
In a preclinical in vivo experiment, they xenografted nude mice intracranially with aggressively growing human glioblastoma cells, then treated them with E6. This resulted in some limited antitumor and anti-angiogenesis effects, but didn't hinder tumor progression. Then they added cisplatin, a powerful cytotoxic agent that disrupts DNA synthesis. That combination inhibited in vivo growth of the glioblastoma cells by 90 percent, with no toxic side effects - but did not lead to outright regression.
The researchers' report of this feat appears in the Proceedings of the National Academy of Sciences (PNAS), dated July 18, 2000, under the title: "A peptide derived from the non-receptor-binding region of urokinase plasminogen activator inhibits glioblastoma growth and angiogenesis in vivo in combination with cisplatin."
Urinalysis In Autistic Children Treated With Secretin Hormone Finds Metabolic Basis For Their Psychosis
Autism is not a punning adolescent cajolery to borrow Dad's car keys. Quite the contrary, it's a severe, lifelong psychosis, beginning in earliest childhood, with a bewildering array of heartbreaking signs and symptoms - from speech disorders to social withdrawal to strange behavior. With 400,000 to 500,000 patients in the U.S. alone, autism is the third most common developmental disability in this country. And there's no approved treatment for it. (See BioWorld Today, March 11, 1999, p. 3.)
But early this month in Boston, on Aug. 5 and 6, five research groups reported to the World Congress of Pediatric Gastroenterology on clinical studies of secretin, a natural intestinal hormone, in treating autistic children. The seemingly improbable link between gut and brain was discerned serendipitously by a mother whose autistic son suddenly sprouted speech abilities and social relationships after he was prescribed secretin for severe digestive illness. It went public on the TV show "Dateline."
Repligen Corp., of Needham, Mass., acquired worldwide exclusive rights to the ensuing secretin patent for its autism indication. Company researchers told the Pediatric Congress that in a Phase I study, a subset of autistic children showed changes in their urinary metabolic profiles as a result of secretin therapy. Repligen is currently conducting a Phase II, placebo-controlled, five-center clinical trial of secretin in young children with autism.
Walter Herlihy, president and CEO of Repligen, learned about secretin as a means of helping his 7-year-old autistic daughter. "We heard about it on the Internet," he observed, "and our ears perked up. We were convinced there was an effect that was not imaged."