By David N. Leff
Editor's note: Science Scan is a roundup of recently published, biotechnology-relevant research.
Designer mice engineered to mimic a particularly pitiless form of childhood blindness - Leber's congenital amaurosis (LCA) - showed signs of improvement after swallowing an oral derivative of vitamin A. About one in 10 young people condemned to blindness owe their loss of vision to LCA.
The unprecedented therapy is reported in the Proceedings of the National Academy of Sciences (PNAS), dated July 18, 2000. Its title: "Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness." Research ophthalmologists at the University of Washington, Seattle, and the Scheie Eye Institute at the University of Pennsylvania, Philadelphia, are the principal co-authors of the feat.
LCA is a rare disorder - for a good reason. It arises from mutations in genes residing in the mammalian mitochondrion. The cytoplasm of every normal cell swarms with several hundred of these freakish organelles, which broker the delivery of energy to the body's tissues. Each mitochondrial genome encodes precisely 13 proteins, but - curiouser and curiouser - 90 percent of its proteins are expressed by genes in the cell's nucleus.
LCA denotes a group of autosomal recessive diseases that cause degeneration of the eye's retina. This leads to rapid loss of vision at birth or early in childhood. The co-authors of this PNAS paper had LCA-afflicted mice swallow doses of 9-cis-retinol, a derivative of vitamin A. They report that treated mice experienced "a profound restoration of vision." In contrast, control animals had little or no eyesight improvement.
Three years ago, researchers at The Foundation Fighting Blindness, headquartered in Hunt Valley, Md., discovered mutations in a gene called RPE65, which, when mutated, accounts for an estimated 10 percent of all LCA cases. They then constructed a transgenic mouse line lacking this gene function. The protein the normal gene encodes is abundantly expressed in cells adjoining the neural retina called the retinal pigment epithelium (RPE). These cells provide nutrients to photoreceptor cells in the retina, and convert vitamin A into a chemical that combines with a molecule in these photroreceptors to form rhodopsin. (See BioWorld Today, Dec. 28, 1998, p. 1.)
By making 9-cis-retinal directly available to RPE cells, the co-authors overcame the effects of RPE65 dysfunction, allowing the retinas of the mice to produce an artificial rhodopsin that restored their vision.
Leber's congenital amaurosis is a rare variant of the far commoner eye disease, retinitis pigmentosa (RP). Researchers have reported that 2 percent of children with early-onset RP had defective RPE65 genes, but in LCA the rate was 16 percent. As reported in the PNAS paper, an 11-year-old girl with LCA from infancy, and consequent loss of peripheral vision, was found to have a homozygous 20-base-pair deletion in her RPE65 gene. Both of her parents and a sibling were heterozygous for the defect.
The Foundation Fighting Blindness financed the PNAS study. Its chief scientific officer, Gerald Chader, stated that "restoration of lost vision in an animal model with a severe retinal degenerative disease offers hope that we may be able to develop sight-restoring treatments for other forms of retinal degeneration before retinal cells die. With advances in genetic research, we are at last able to understand the causes of vision loss and develop treatments that overcome a gene defect."
Adding Interleukin-2 Treatment To HAART's Anti-HIV Regimen Boosted T Cells' CD4+ Levels
Is HAART enough? The current, widespread "highly active antiretroviral therapy" knocks the AIDS virus down but not out. The first randomized, controlled trial of interleukin-2 (IL-2) therapy combined with HAART markedly boosted CD4+ without increasing HIV levels in patients' blood.
Results of the eight-center trial are reported in the Journal of the American Medical Association (JAMA), dated July 12, 2000, under the title: "Immunologic and virologic effects of subcutaneous IL-2 treatment in combination with antiretroviral therapy: A randomized controlled trial." Its authors are at NIH's National Institute of Allergy and Infectious Diseases (NIAID).
That two-year clinical trial, from April 1996 to April 1998, enrolled 78 HIV-infected volunteers already on the HAART regimen, half of whom had IL-2 added to their therapy. After one year of treatment, those in the IL-2 add-on group had an average 112 percent jump in their CD4+ counts, compared with 18 percent in the HAART-only control cohort. Moreover, their viral load in blood declined slightly.
IL-2 is produced by T cells - HIV's target. It potently enhances immune defenses, mainly T cells, B cells and natural killer cells. "The ultimate role of IL-2," observed the JAMA paper's senior author, "if it is found to benefit patients on antiretroviral therapy, would be to offer yet another means of maintaining quality of life and decreasing the incidence of AIDS-defining events. That is the goal. That is the hope."
Proprietary Cell Pathways Drug Instigates Assisted Tumor Suicide In Multiple Cancers
In the war on cancer, death is a much-desired outcome - the death of tumor cells, that is. In cancer chemotherapy, many of the drugs in use bluntly kill fast-dividing cells, which by definition are usually cancerous ones. The July 1, 2000, issue of the journal Cancer Research reports a different strategy - forcing the target cells to commit suicide - that is, apoptosis.
The article's title reads: "Exisulind induction of apoptosis involves guanosine 3',5'-monophosphate [GMP] phosphodiesterase [PDE] inhibition, protein kinase G activation, and attenuated b-catenin." Its principal authors are scientists at Cell Pathways Inc. in Horsham, Pa.
Working backward through the title's run-up to cell death by apoptosis, beta-catenin is a regulatory protein that causes excessive cell growth in colon cancer. There it accumulates unduly when mutations occur in the gene for adenomatous polyposis coli. This is the non-malignant precursor to colon cancer per se. At the title's beginning, exisulind (trademarked Aptosyn) is a proprietary Cell Pathways drug, a non-steroidal, anti-inflammatory agent. In between are the PDE gene families, overexpressed in cancerous and precancerous cells of the colon.
Inhibiting this chain of events ends up with the programmed cell death of the tumor-tainted cells, while sparing normal ones.