Nanotechnology, gene therapy, implants are the future of ocular disease treatment

Issue: March 2006

ByBarbara Anan Kogan, OD

ORLANDO, Fla. – Here at the fourth annual Contact Lens and Eyecare Symposium (CLES), newly elected Contact Lens Association of Ophthalmologists (CLAO) president, William Ehlers, MD, reported that nanotechnology, contact lens research, gene therapy, injections, implants and oral delivery modalities are all allowing for the development of new treatments for anterior and posterior ocular conditions.

“Understanding the mechanisms and disease processes is enabling us to meet patients’ needs as well as conduct stem cell research to regulate these mechanisms,” he told Primary Care Optometry News. Dr. Ehlers is also an assistant professor at the University of Connecticut’s Health Center, Farmington.

AMD treatments in development

Sirna-027 (Sirna Therapeutics, San Francisco) uses small interfering RNA (siRNA) molecules to specifically inhibit genes in the angiogenic pathway with nanoparticles delivered intravitreally. Visual acuity increased in phase 1 clinical trial subjects, while mRNA vascular endothelial growth factor (VEGF-1) was inhibited. Age-related macular degeneration-causing genes are selectively targeted.

“Nanotechnology’s possible advantages include less systemic absorption, with potential applications for dry eye, corneal infections, glaucoma and other conditions,” Dr. Ehlers said in his lecture. He told Primary Care Optometry News that he anticipated nanotechnology to become a treatment modality in the eye care practitioner’s office within 3 to 5 years.

The LentiVector delivery system, RetinoStat, by Oxford BioMedica (London), blocks AMD’s angiogenesis genes, endostatin and angiostatin. Choroidal angiogenesis blockage significantly reduced choroidal neovascularization by 50% to 60% and blood vessel leakage by 24% to 26%, according to a presentation at the Association for Research in Vision and Ophthalmology meeting, 2005. RetinoStat wet AMD clinical trials are scheduled to begin this year or next.

RTP801i gene therapy (Quark Biotech, Fremont, Calif.), with its modified siRNA, targets hypoxia that may regulate the pathogenesis for VEGF, AMD and diabetic retinopathy, independent of growth factors, according to Dr. Ehlers. Injected intravitreally, RTP80li significantly reduced retinal blood vessel leakage in a company-sponsored trial, enabling a Food and Drug Administration investigational new drug filing.

The Montreal-based neuroscience company, BioAxone Therapeutic, which engineered protein BA-210 and kinase antagonist BA-1049 for AMD and glaucoma, is now using its lead compound, recombinant protein Cethrin, in phase 1 and 2 trials to protect and regenerate neurons against wet AMD angiogenesis, Dr. Ehlers said.

Uveitis therapy research

FDA phase 3 trial results indicate that Vitrase (ovine hyaluronidase, ISTA Pharmaceuticals) may be used earlier to reduce diabetes mellitus-related vitreous hemorrhage. Dr. Ehlers reported that best-corrected visual acuity after one in-office intravitreal injection increased by three or more lines as early as 1 month.

According to Dr. Ehlers, phase 1 and 2 trials being conducted at the National Eye Institute are examining whether the combination of daclizumab antibody, which is designed to prevent a chemical interaction necessary for lymphocyte immune cells to produce the inflammation associated with uveitis, and the immune suppressing drug, sirolimus, can further control lymphocyte activity. The daclizumab is administered subcutaneously for 52 weeks with a 6-mg oral sirolimus dose 1 to 2 days after the initial injection. Pilot study results are anticipated in 6 to 9 months, after which a clinical study will investigate the ability for patients to discontinue uveitis medication.

Dry eye therapies

ISTA Pharmaceuticals (Irvine, Calif.), with Japan’s Senju, which manufactures an oral mucin secretagogue for stomach ulcers, is nearing completion of phase 2 clinical trials for ophthalmic topical administration of ecabet sodium, Dr. Ehlers told Primary Care Optometry News. “This is designed to increase both the quantity and quality of the conjunctiva’s mucin layer,” he said.

Researchers at Alcon Laboratories (Fort Worth, Texas) are using a rabbit model to conduct pre-phase 1 clinical trials for 15(S)-HETE (15-hydroxy eicosatetraenoic acid) as a selective mucin secretagogue. Production of glycoprotein Muc1, an important mucin layer component that may help restore corneal integrity in dry eye patients, is stimulated. Alcon trials show a 71% decrease in corneal staining and no thinning of pre-corneal tear film over a 4-hour period of desiccation, Dr. Ehlers reported.

Alimera Sciences’ (Boston) Soothe, which was co-invented by Donald R. Korb, OD, director of research at Ocular Research of Boston, restores the lipid layer thickness by 100%, said Dr. Ehlers, while relieving dry eye discomfort.

Advanced Vision Research’s (Woburn, Mass.) TheraTears Nutrition, developed by Jeffrey Gilbard, MD, is designed to increase tear secretion in posterior blepharitis or meibomianitis. It is available as an oral dietary supplement or topical liquid form of the omega-3 essential fatty acids (EFAs) flaxseed (alpha-linolenic acid) and fish oils to function as anti-inflammatory dry eye agents, and the omega-6 fatty acid, gamma linolenic acid (GLA).

For more information:

William Ehlers, MD, is an assistant professor at the University of Connecticut Health Care Center. He can be reached at 263 Farmington Ave., Farmington, CT 06030-6227; (860) 679-1390; fax: (860) 679-3540; e-mail: ehlers@adp.uchc.edu.

Barbara Anan Kogan, OD, can be reached at 4501 Connecticut Ave. NW, Suite 102, Washington, DC 20008-3711; phone/fax: (202) 244-1324; e-mail: bakogan@mindspring.com.

Suggested reading:

Shen J, Samul R, Silva RL et al. Suppression of ocular neovascularization with siRNA targeting VEGF receptor 1. Gene Therapy 2006;13(3):225-234; www.nature.com/gt/journal/v13/n3/abs/3302641a.html.