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Archive - Aug 1, 2015

Vision-Restoring Retinal Gene Therapy Also Strengthens Visual Processing Pathways in Brain; Rapid Regrowth of Unused Brain Connections Seen After Decades of Near Blindness in Treated LCA2 Patients

Since 2007, clinical trials using gene therapy have resulted in often-dramatic sight restoration for dozens of children and adults who were otherwise doomed to blindness. Now, researchers from the Perelman School of Medicine at the University of Pennsylvania (Penn) and The Children’s Hospital of Philadelphia (CHOP), together with colleagues, have found evidence that this sight restoration leads to strengthening of visual pathways in the brain, published in the July 15, 2015 issue of Science Translational Medicine. The article is titled “Plasticity of the Human Visual System after Retinal Gene Therapy in Patients with Leber’s Congenital Amaurosis.” “The patients had received the gene therapy in just one eye (their worse seeing eye), and though we imaged their brains only about two years later, on average, we saw big differences between the side of the brain connected to the treated region of the injected eye and the side connected to the untreated eye,” said lead author Manzar Ashtari, Ph.D., Director of CNS Imaging at the Center for Advanced Retinal and Ocular Therapeutics in the Department of Ophthalmology at Penn. Ashtari is the former Director of Diffusion Tensor Image Analyses and Brain Morphometry at CHOP. “It’s an elegant demonstration that these visual processing pathways can be restored even long after the period when it was thought there would be a loss of plasticity,” said senior author Jean Bennett, M.D., Ph.D., the F.M. Kirby Professor of Ophthalmology at Penn and Director of the Center for Advanced Retinal and Ocular Therapeutics. The team examined ten patients who have Leber’s congenital amaurosis Type 2 (LCA2), a rare disease that afflicts those who inherit one bad copy of an LCA2 gene from each parent.

NIH Images Show How Neurotensin Hormone May Activate Its G-Protein-Coupled Receptor (GPCR); Binding Changes GPCR Shape and It Moves Through Membrane into Cell to Likely Activate G Proteins

Many hormones and neurotransmitters work by binding to receptors on a cell's exterior surface. This activates the receptors causing them to twist, turn, and spark chemical reactions inside cells. NIH scientists used atomic level images to show how the neuropeptide hormone neurotensin might activate its receptors. Their description is the first of its kind for a neuropeptide-binding G protein-coupled receptor (GPCR), a class of receptors involved in a wide range of disorders and the target of many drugs. "G protein-coupled receptors are found throughout the body. Knowing how they work should help scientists devise better treatments," said Reinhard Grisshammer, Ph.D., an investigator at the NIH's National Institute of Neurological Disorders and Stroke (NINDS) and the senior author of the study published online on July 24, 2015 in an open-access article in Nature Communications. The article is titled “Structural Prerequisites for G-Protein Activation by the Neurotensin Receptor.” Neurotensin is believed to be involved in Parkinson's disease, schizophrenia, temperature regulation, pain, and cancer cell growth. Previously, Dr. Grisshammer and his colleagues showed how neurotensin binds to the part of its receptor located on a cell's surface. In the current study, the scientists demonstrated how binding changes the structure of the rest of the receptor, which then passes through a cell's membrane and into its interior. There, neurotensin receptors activate G proteins, a group of molecules inside cells that control a series of chemical chain reactions. For these experiments, scientists shot X-rays at crystallized neurotensin receptor molecules. Making crystals of receptors that activate G proteins is difficult. In most studies, scientists have investigated inactive receptors.