Retina Researchers Bullish on Bear Bile
Whether the causes of vision loss lie in the retina, the optic nerve or the brain, they share a common endpoint: apoptosis of irreplaceable cells. Yet most of the potential molecular therapies for ocular diseases seek to arrest events earlier in the degenerative process. Until such therapies emerge, wouldn??‚??„?t it be great to have a stopgap, a way to throw a monkey wrench into the mechanics of programmed cell death?
That??‚??„?s what a group of researchers at Emory University might have found??‚??€even if their idea seems a little wild, and even if it??‚??„?s a few thousand years old.
The group concluded that a synthetic version of a bile acid found mainly in certain species of bears protected from apoptosis both genetically impaired photoreceptors and those that are stressed.
Normally, knockout retinitis pigmentosa mice have profound visual loss by 18 days after birth. However, when the mice received three injections of the synthetic bile acid over 10 days, their retinas appeared nearly normal on day 18, and amplitudes on electroretinograms were greater than those of the gene-deficient controls.
In a light-toxicity study on healthy mice with normal retinas, the control group showed extensive damage throughout nearly the entire nuclear layer 15 days after exposure, but the treated mice had normal-appearing and -functioning retinas, the researchers write.1
??‚??“What we??‚??„?re looking at is the possibility of a very broad spectrum antiapoptotic, which is critical since every single retinal degeneration appears to involve apoptosis. The drug is relatively cheap, well-tolerated, and it seems to be having really big effects,??‚? said principal investigator Jeffrey Boatright, PhD, assistant professor of ophthalmology at Emory University.
The bile component under study is tauroursodeoxycholic acid (TUDCA) and its unconjugated form, ursodeoxycholic acid (UDCA). These constitute about 5 percent of the bile acids in humans but a much greater proportion in bears that hibernate, such as the black, brown and Kodiak species. Natural bear bile has been a traditional remedy in China for vision ailments for 3,000 years. Its use continues despite the wide availability of the synthetic form.
In the United States, synthetic UDCA was approved in 1987 as an oral drug, called ursodiol, to treat patients with cirrhosis. Along with TUDCA, it has been shown to protect neurons in models of stroke, Parkinson??‚??„?s and Huntington??‚??„?s diseases??‚??€but not for ocular use.
??‚??“If protecting ocular cells with these bile acids is not a crazy idea, then why hasn??‚??„?t it been studied before? Where has this ??‚??œwonder drug??‚??„? been all our lives???‚? Dr. Boatright asked. ??‚??“The short answer is that the work actually has been done before, but there were a lot of hints that were misinterpreted.??‚? Dr. Boatright and his colleagues plan to bring TUDCA out of the closet with further study.
1 Boatright, J. H. et al. Mol Vis 2006;12:1706??‚??€œ1714.
Glaucoma Meds for Retina?
Don??‚??„?t blink??‚??€you might miss another milestone in the fast-moving race to discover the molecular reasons for sight-threatening retinal diseases.
One of the most exciting developments so far this year came in a paper published in Nature Medicine1 suggesting that medications similar to those already used against glaucoma might be able to halt the vascular leakage underlying diabetic macular edema (DME).
Led by the proteome research unit at Boston??‚??„?s Joslin Diabetes Center, the scientists isolated 117 proteins from vitreous samples taken during 25 vitrectomies. The patients were diabetics with and without proliferative retinopathy, and a nondiabetic control group.
After proteomic and bioinformatics analyses identified vitreous protein abnormalities in people with proliferative retinopathy, and after a series of supporting rodent experiments, the researchers had strong evidence for a completely new cause of vascular leakage and macular edema: elevated carbonic anhydrase isoform I (CA-I) in the vitreous.
In the retinas of individuals with diabetes, red blood cells from small hemorrhages release CA-I into the vitreous, raising the pH, the experiments showed. This in turn apparently sets off a molecular cascade that ultimately causes blood vessel leakage by activating bradykinin, a vasoactive and proinflammatory molecule.
Furthermore, intracranial injection in rats of CA-I increased vascular permeability in the brain, suggesting that this same enzymatic pathway could lead to brain edema associated with cerebral hemorrhage, said Edward P. Feener, PhD, the principal investigator.
The study found that the vitreal concentrations of CA-I were 15.3 times higher in eyes with proliferative diabetic retinopathy (PDR) than in nondiabetics (P < 0.01). The PDR eyes also showed 8.2 times as much CA-I as did diabetic eyes with no disease (P < 0.05).
CA-I was also elevated in eyes with nonproliferative diabetic retinopathy, suggesting that the appearance of CA-I in the vitreous was not solely due to bleeding from nascent vessels, but can occur from other sources of intraocular hemorrhage associated with retinopathy. Another isoform, CA-II, also was elevated in the PDR eyes.
??‚??“Our study indicates that retinal hemorrhage may be altering the protein composition in the eye, and this may play an active role in a chronic inflammatory state on the retina,??‚? Dr. Feener said ??‚??“This area hasn??‚??„?t had that much attention in the field of eye research, but it??‚??„?s a prominent field in cerebrovascular research. It may be that some of those components apply to the retina.??‚?
An accompanying commentary by two Pennsylvania State University researchers agreed.2 The authors noted that there had been no previous suspicion that CA-I might raise vascular permeability. The Joslin-led group showed ??‚??“the power of an unbiased proteomic analysis,??‚? the Penn State scientists write. ??‚??“They fundamentally expand the understanding of diabetic retinopathy and provide new clues to potential therapy.??‚?
In addition to trying to inhibit CA-I , drug developers could try to block other molecules downstream of the CA-I-initiated enzymatic pathway, Dr. Feener said. The kallikrein-bradykinin pathway is an emerging area for drug development, he said.
However, deactivating CA-I and CA-II would require a drug other than the two CA inhibitors used for glaucoma, acetazolamide and dorzolamide. Although those drugs potently inhibit two isoforms, CA-IV and CA-XIV, they are less effective with CA-I and CA-II, he said.
1 Gao, B. B. et al. Nat Med 2007;13(2):181??‚??€œ188.
2 Gardner, T. W. and D. A. Antonetti. Nat Med 2007;13(2):131??‚??€œ132.
Ophthalmology World News
Older Kids and Cataract: Lens Removal Worthwhile
The next time you go on an ophthalmic mission to a medically underserved nation, don??‚??„?t assume that older children won??‚??„?t benefit from having their congenital cataracts removed, says vision science researcher Pawan Sinha, PhD.
It turns out that the ??‚??“critical period??‚? for acquiring vision isn??‚??„?t so critical after all, Dr. Sinha is finding in his research in India.
??‚??“If an ophthalmologist just looks at the Snellen acuity of an older child after surgery, the results might seem disappointing,??‚? Dr. Sinha said. ??‚??“You might think the surgery was useless. But these children gain a surprising amount of visual function, and it continues to improve over time.??‚? Dr. Sinha came to this conclusion because of a project that sprang four years ago from his head and his heart. As an associate professor of brain and cognitive sciences at the Massachusetts Institute of Technology, Dr. Sinha has a professional interest in finding out how humans learn to recognize objects, not an easy field since babies are usually the experimental subjects.
Meanwhile, he personally was moved by the numbers of congenitally blind children who go untreated in his native country of India. ??‚??“And the idea clicked that we could handle both the humanitarian need and the research need at the same time,??‚? he said.
His Project Prakash (??‚??“light??‚? in Sanskrit) now supports ophthalmic surgery for Indian children who couldn??‚??„?t get treatment for reversible vision problems as infants. His group studied how the patients, some of whom are in their teens, learn to recognize objects with their newfound??‚??€if limited??‚??€vision.
The ??‚??“critical period??‚? theory of visual acquisition can fool physicians into not supporting surgery in older children, especially if the crush of patients prevents them from doing follow-up exams, Dr. Sinha said. But ophthalmologists who find time to reexamine the children over time likely will be surprised at the visual system??‚??„?s apparent plasticity, he added.
??‚??“Once they do that, the doctors now tell me that they are amazed by these children. Even though their acuity measures on a chart might still be compromised, their ability to do things with that limited acuity can be quite good,??‚? he said.
Mutation That??‚??„?s Bad for Eye Is Bad for Placenta
The tumor-suppressor gene associated with retinoblastoma also plays a critical role in the development of a placenta capable of supporting an embryo through a full term of pregnancy, research at Ohio State University concluded.
A team led by Gustavo Leone, PhD, assistant professor of molecular virology, immunology and medical genetics, demonstrated in mice that the Rb gene is essential to the development of trophoblast stem cells into a normal, healthy placenta.1
??‚??“Our findings strongly suggest that the Rb gene is important in the development of the placenta, but they have other important implications, as well,??‚? said Dr. Leone, who is a researcher with Ohio State??‚??„?s human cancer genetics program. ??‚??“People born with one mutated Rb gene have a higher risk of developing retinoblastoma. But are they also predisposed to miscarriage? Do Rb-related defects in the placenta cause learning or physical abnormalities? We are investigating these questions now.??‚?
Working with mice, the research team developed a transgenic mouse that, without the Rb gene in the trophoblast stem cells that give rise to the placenta, produced a placenta in which cells divided too much and organized themselves poorly. The embryos died four days short of their 19-day gestation period. The critical variable was the presence of Rb in the initial stem cells. If these cells had the Rb gene but their daughter cells did not, the placenta formed normally and the embryos didn??‚??„?t die.
Dr. Leone and colleagues now are working to determine whether lack of the Rb gene leads to miscarriages. ??‚??“Miscarriages have never been linked to a gene defect, but understanding the genetic basis of miscarriage would be a hugely important,??‚? he said.
1 Wenzel, P. L. et al. Genes Dev 2007;21:85??‚??€œ97.