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Biosynthetic Corneas Stimulate Regrowth
Canadian and Swedish researchers have become the first to use a cornea fabricated from recombinant human collagen such that it integrates with the human eye, stimulates regeneration and improves vision.1 Ten patients with advanced keratoconus or central corneal scarring participated in the phase 1 trial.
“Scientists at FibroGen [a biotech company in San Francisco] inserted a human collagen gene into yeast cells and got them to produce the protein,” said May Griffith, PhD, MBA. The collagen produced was purified, tested, chemically treated and then shaped with a modified contact lens mold, she said. Dr. Griffith is senior scientist at the Ottawa Hospital Research Institute, professor of ophthalmology and cellular and molecular medicine at the University of Ottawa, and professor of regenerative medicine and director of the Integrative Regenerative Medicine Centre at Linköping University in Linköping, Sweden.
“What we got was something that looks like a contact lens but is the shape and size of a normal human cornea,” said Dr. Griffith. She collaborated with Linköping University eye surgeon Per Fagerholm, MD, PhD, who removed damaged corneal tissue from the patients and replaced it with the biosynthetic corneal implant that was then sutured into place.
Once there, it acted as a scaffold into which the patient’s own cells grew, producing a functioning cornea. The cells grew in quickly, but hit both a proverbial and literal bump in the road—sutures—which posed an obstacle for epithelial migration and led to localized implant thinning and fibrosis in some patients. Once the sutures were removed, however, healing regained momentum. In addition, gas-permeable rigid contact lenses compensated for any eye surface roughness and enhanced vision in all 10 patients, making improvement in vision comparable to that in patients who have conventional transplants. Prior to surgery, the patients were contact lens intolerant.
Despite initial visual shortcomings—four of the 10 did not have improved vision without placement of contact lenses—the implant’s safety profile was better than expected. Patients experienced no severe complications, such as stromal edema, neovascularization, glaucoma or prolonged inflammation, and they required no long-term steroid immunosuppression.
Efficacy data were also surprising. Regeneration of nerves occurred as early as three months with the subbasal nerve plexus appearing in nine of 10 patients by 24 months. Becoming sensitive to touch, the new corneas enabled the autonomic production of tears.
“The theory was that patients’ own cells would come in and produce collagen,” said Dr. Griffith, explaining that continually improving vision, even 2.5 years out, adds credibility to the idea that remodeling is occurring—a trend researchers will more closely track with future studies. In addition, future suturing will steer clear of the middle of the cornea. To further lessen complications, the researchers may explore sutureless methods.
1 Fagerholm, P. et al. Sci Transl Med
Dr. Griffith reports no financial interests.
Retinitis Pigmentosa Drug Goes to Trials
Buoyed by the results of a small, retrospective case review, the Foundation Fighting Blindness will spend $2.1 million over the next three years to find out whether valproic acid really does prevent photoreceptor death in retinitis pigmentosa.
Valproic acid is a histone deacetylase (HDAC) inhibitor that is available as an FDA-approved generic medication for controlling epileptic seizures and the manic phase of bipolar disorder.
And over the last decade, there has been burgeoning interest in other, off-label uses of it and of other HDAC inhibitors for applications, including:
- protecting cells from ischemic and inflammatory damage that triggers cell damage in the retina and elsewhere.1,2
- halting rampant cell proliferation and, potentially, frank neoplastic disease.3
“You may not need to know the genotype to protect the retina with HDAC inhibition,” said Shalesh Kaushal, MD, PhD, chair of ophthalmology and associate professor of ophthalmology and cell biology at the University of Massachusetts in Worcester. “If you broadly characterize retinal diseases, all of them involve fundamental biological events: inflammation, complement activation, oxidative stress and cell death. Valproic acid affects all these underlying events,” he said.
Dr. Kaushal was the senior author of the recently published pilot study of the off-label use of valproic acid to protect photoreceptors in RP.4 The retrospective study found that five of seven RP patients, whom Dr. Kaushal treated while working at the University of Florida, had improved visual fields after taking 500 to 750 mg of valproic acid daily for two to six months.
Side effects were mild (tiredness and stomach irritation). The average logMAR change was -0.172 ± 0.269 (range -0.824 to 0), equivalent to improving the Snellen score from about 20/47 to 20/32. Assuming no loss in acuity without treatment, the improved VA was judged statistically significant (p < 0.02).
“To the best of our knowledge, this is the first reported case of improvement of vision function in patients with RP as a result of pharmacological treatment,” the researchers write.
The next step will be a three-year, placebo-controlled, randomized clinical trial of valproic acid as RP therapy, for which the University of Massachusetts will be the coordinating center. The 90-subject study is funded by the Foundation Fighting Blindness’ newly created National Eye Evaluation Research Network. Patients will also be recruited at the University of Utah and the Retina Foundation of the Southwest, in Dallas.
But Dr. Kaushal said that, based on research and his clinical experience, he is comfortable using valproic acid off-label in RP patients who decline to participate in the trial.
Dr. Kaushal has intellectual property for the use of valproic acid and other HDAC inhibitors for retinal diseases. His lab is exploring the use of novel HDAC inhibitors.
1 Wallace, D. M. and T. G. Cotter. J Neurosci Res
2 Sailhamer, E. A. et al. Surgery
3 Göttlicher, M. Ann Hematol
2004;83 Suppl 1:S91–92.
4 Clemson, C. M. et al. Br J Ophthalmol
2010. Available at www.ncbi.nlm.nih.gov/pubmed/20647559
Medical Therapy Slows Diabetic Retinopathy
Intensive glycemic control and lipid-reduction therapy can slow the progression of diabetic retinopathy in older patients with type 2 diabetes and established cardiovascular risk factors. However, intensive blood-pressure control has no effect on DR progression in these high-risk patients. That’s the take-home message from the ACCORD Eye Study, a subset of the landmark ACCORD (Action to Control Cardiovascular Risk in Diabetes) clinical trial.
The full ACCORD trial enrolled 10,251 adults with type 2 diabetes who were at high risk for serious cardiovascular events. The study compared standard medical therapy with three intensive therapies—controlling blood sugar to near-normal levels, controlling blood pressure to near-normal levels and treating high lipid levels with a combination of fenofibrate and simvastatin.
For the ACCORD Eye Study, researchers evaluated a subgroup of 2,856 participants. 1 At four years, the rates of DR progression were as follows:
- 7.3 percent with intensive glycemia treatment (hemoglobin A1c levels < 6.0 percent), vs. 10.4 percent with standard therapy (7.0 to 7.9 percent) (p = 0.003);
- 6.5 percent with fenofibrate/ simvastatin, vs. 10.2 percent for simvastatin alone (p = 0.006); and
- 10.4 percent with blood-pressure control (< 120 mmHg), vs. 8.8 percent with standard therapy (< 140 mmHg) (p = 0.29).
“These study results give physicians increasing evidence that treatment of people with diabetes by intensive glycemic control and combination lipid therapy with fenofibrates and statins can reduce the risk of diabetic retinopathy progression,” said Emily Y. Chew, MD, deputy director of the NEI’s division of epidemio- logy and clinical applications. However, she cautioned, “The risks and benefits of these therapies need to be weighed against a patient’s health needs and expectations.” In particular, the ACCORD trial found that intensive glycemic control increases the risk of hypoglycemic events and death.
The next step? “There is a lot of subanalysis left to do,” said Dr. Chew. “We want to take a look at a number of issues, including macular edema, the effect on vision over time and the need for procedures such as vitrectomy and panretinal photocoagulation.”
1 Chew, E. et al. New Engl J Med
Watch for IFIS in Women
With cataract surgeons now screening men for tamsulosin use, the link between intraoperative floppy iris syndrome (IFIS) and an alpha1 adrenoreceptor antagonist is old news, right? Not if the patient is female, and not if she takes the alpha1 antagonist doxazosin (Cardura) for systemic hypertension, suggests a preliminary British study.1 The IFIS prevalence that Antonis Ioannides, MBBS, found in 713 women—2.8 percent—is higher than the figure initially reported for men in 2005 (2 percent) after a similar case study of tamsulosin (Flomax) and IFIS.2 Of the 20 IFIS cases in Dr. Ioannides’ study, 13 were associated with doxazosin (p < 0.01), and seven were not. Thirteen of 25 doxazosin eyes (52 percent) developed IFIS, compared with 35 percent in doxazasin- free diabetic women. (IFIS occurs in 90 percent of tamsulosin users.3)
Dr. Ioannides performed the study while serving as specialty registrar at Mid Essex Hospitals, northeast of London. He now has the same fellowship-level, ophthalmic training designation at Mid Yorkshire Hospitals.
“Most ophthalmologists with whom I have discussed this thought that they needed to look only at men for medication-associated risk of IFIS. But it’s not just men who are at risk, and now we have an identifiable risk factor for women,” Dr. Ioannides said. And if internists were to heed recent research supporting doxazasin as additive hypertension therapy, 4 IFIS in women might increase further, his study suggests.
Dr. Ioannides is conducting a large study. Results could come in 2011.
1 Ioannides, A. ESCRS Poster. Feb. 12–14, 2010.
2 Chang, D. F. and J. R. Campbell. J Cataract Refract Surg
3 Chang, D. F. et al. Ophthalmology
4 Ohta, Y. et al. Hypertens Res
EyeNet thanks Susan B. Bressler, MD, K. David Epley, MD, Christopher Rapuano, MD, and Steven I. Rosenfeld, MD, for their help with this issue’s News in Review.