生物谷报道：来自Pennsylvania大学的科学家们最近证实，用于恢复盲人视网膜活性的基因疗法同样可以恢复大脑视觉中枢的功能——这是产生视觉的关键区域。
这一由Penn医学院的神经学助理教授Geoffrey K. Aguirre领导的多学科小组发现，基因疗法可以恢复天生失明的动物的视网膜、视觉通路和视觉中枢反应，并且可能对人类起到同样的效果。
以上结果支持了用这一治疗视网膜疾病的疗法来进行其它治疗。科学家使用功能核磁共振测量了发生了RPE65基因变异的失明小狗的大脑区域活性，RPE65是视黄醛等物质循环的关键分子。同样的变异在人类中会导致Leber先天性失明，或LCA。这是已知的第一种可用基因疗法治疗的人类视力缺陷。
基因疗法通过将能正常工作的RPE65基因导入视网膜，来恢复犬类眼睛的正常功能。但是在这之前，科学家并不清楚大脑是否可以接受到这些画面。
小组发现，基因疗法可以大大提高大脑视觉中枢对于光的反应。在失明4年的小狗中，大脑视觉功能得到了恢复，并且这种恢复在另一只小狗中已经维持了至少2年半，这表明此种疗法的持久性。
Penn的科学家因此研究了同种失明的人类病人的大脑视觉中枢。RPE65变异的年轻病人有着完整的视觉中枢通路和近乎正常的结构。Penn小组同时发现，尽管这些LCA病人对于微弱的光线没有反应，但是对于明亮的光源他们的反应和正常人却差不多。
相关英文原文：
Gene therapy awakens the brain despite blindness from birth
Researchers at the University of Pennsylvania have demonstrated that gene therapy used to restore retinal activity to the blind also restores function to the brain's visual center, a critical component of seeing. The multi-institutional study led by Geoffrey K. Aguirre, assistant professor of neurology in Penn's School of Medicine, shows that gene therapy can improve retinal, visual-pathway and visual-cortex responses in animals born blind and has the potential to do the same in humans.
"The retina of the eye captures light, but the brain is where vision is experienced," Aguirre said. "The traditional view is that blindness in infancy permanently alters the structure and function of the brain, leaving it unable to process visual information if sight is restored. We've now challenged that view."
The results support the potential for human benefit from retinal therapies aimed at restoring vision to those with genetic retinal disease. Researchers used functional MRI to measure brain activity in blind dogs born with a mutation in gene RPE65, an essential molecule in the retinoid-visual cycle. The same mutation causes a blindness in humans called Leber congenital amaurosis, or LCA. It is the first human eye-retinal disorder slated for gene therapy.
Gene therapy, performed by introducing a working copy of RPE65 into the retina, restored eye function in canines. Yet, it was previously unclear if the brain could "receive" the restored sight.
The team found that gene therapy to the eye dramatically increased responses to light within the visual cortex of the canine brain. The recovery of visual brain function occurred in a canine that had been blind for the first four years of its life, and recovery was found to persist in another dog for at least two-and-a-half years after therapy, suggesting a level of permanence to the treatment.
Penn scientists then studied the structure and function of the visual brain of human patients with the same form of blindness. Young adults with blindness from RPE65 mutation had intact visual brain pathways with nearly normal structure. The Penn team also found that, while the visual cortex of these patients with LCA did not respond to dim lights, the brain's reaction to brighter lights was comparable to that of individuals with normal sight.
"It seems these patients have the necessary brain pathways ready to go if their eyes start working again," Aguirre said.
The results of the current study are critical to these human clinical trials, led at Penn's Scheie Eye Institute by Samuel G. Jacobson, professor of ophthalmology, and Artur V. Cideciyan, research associate professor of ophthalmology.
"Existence of functional potential both in the eye and brain are prerequisites for successful gene therapy in all forms of LCA," Cideciyan said. "In the RPE65 form of the disease, we now have evidence for both, and treatment at the retinal level has the hope of recovery of useful vision in patients."
Findings of the study were reported in the journal PLoS Medicine.
原始出处：
Canine and Human Visual Cortex Intact and Responsive Despite Early Retinal Blindness from RPE65 Mutation
Geoffrey K. Aguirre1*, András M. Komáromy2, Artur V. Cideciyan3, David H. Brainard4, Tomas S. Aleman3, Alejandro J. Roman3, Brian B. Avants5, James C. Gee5, Marc Korczykowski1, William W. Hauswirth6, Gregory M. Acland7, Gustavo D. Aguirre2, Samuel G. Jacobson3
1 Department of Neurology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 2 Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 3 Department of Ophthalmology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 4 Department of Psychology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 5 Department of Radiology, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America, 6 Department of Ophthalmology, University of Florida, Gainesville, Florida, 7 Baker Institute, College of Veterinary Medicine, Cornell University, Ithaca, New York, United States of America
Background
RPE65 is an essential molecule in the retinoid-visual cycle, and RPE65 gene mutations cause the congenital human blindness known as Leber congenital amaurosis (LCA). Somatic gene therapy delivered to the retina of blind dogs with an RPE65 mutation dramatically restores retinal physiology and has sparked international interest in human treatment trials for this incurable disease. An unanswered question is how the visual cortex responds after prolonged sensory deprivation from retinal dysfunction. We therefore studied the cortex of RPE65-mutant dogs before and after retinal gene therapy. Then, we inquired whether there is visual pathway integrity and responsivity in adult humans with LCA due to RPE65 mutations (RPE65-LCA).
