Podcasts about rpe65

Jason Comander, Md, PhD, clinical researcher, surgeon, and director of the Inherited Retinal Disease Disorders Service at Mass Eye and Ear, talks to host Ben Shaberman about his administration of LUXTURNA gene therapy to RPE65 patients, his team's re-analysis of vitamin A therapy for retinitis pigmentosa, and passion for retinal research and patient care.

durée : 00:05:25 - Le Reportage de la Rédaction - À l'institut Imagine, situé dans l'hôpital Necker, à Paris, les chercheurs planchent sur les causes génétiques des maladies rares. Deux équipes présentent leurs avancées concernant des maladies de l'oil et du sang. Rediffusion de l'émission du 3 mars 2022 Le 28 février dernier, se tenait la journée mondiale des maladies dites "rares", qui frappent tout de même un bébé sur 2 000 naissances, soit plus de trois millions de personnes en France ! À l'institut Imagine, dans l'enceinte de l'hôpital Necker à Paris où sont regroupés un millier de chercheurs, le travail est axé sur les causes génétiques des maladies rares. Deux équipes ont présenté, ce 28 février, leurs avancées thérapeutiques majeures. L'une concerne des petits enfants, auxquels on parvient à rendre, en partie,  la vue. L'autre concerne des jeunes que l'on est parvenu à délivrer d'une souffrance quotidienne due à des globules rouges qui dysfonctionnent. Les enfants peuvent à nouveau voir dans la pénombre L'Amaurose congénitale de Leber fait partie de la famille des dystrophies rétiniennes. Elle a été décrite pour la première fois au milieu du XIXe siècle, en 1869 précisément, par Theodor Karl Gustav von Leber, un ophtalmologiste allemand qui travailla à Heidelberg et Berlin. À l'époque et pendant un siècle et demi, les petits enfants touchés par cette dégénérescence des cellules de la rétine ne pouvaient espérer de traitement et devenaient progressivement aveugles, dans la petite enfance ou plus souvent au cours de l'adolescence. Or, depuis 2019, une thérapie génique a permis d'enrayer cette maladie très rare, qui touche un bébé sur 35 000 à 50 000.  Plusieurs gènes sont à l'origine de la maladie. Parmi eux, le gène RPE65 - lorsqu'il mute - est responsable de 10% des cas d'Amaurose congénitale de Leber. Ce gène est donc la cause directe d'une cécité progressive que décrit le professeur Matthieu Robert, praticien hospitalier dans le service d'ophtalmologie de l'hôpital Necker-Enfants malades, chercheur à Paris-Saclay, et professeur des universités : Il existe donc à présent un traitement pour éviter cela. Une copie du gène qui fonctionne normalement est introduite derrière la rétine, au contact de l'épithélium pigmentaire. Il faut, pour cela, pratiquer une vitrectomie, c'est-à-dire une opération chirurgicale assez délicate qui implique de retirer le vitré de l'oeil et d'introduire ensuite le gène à l'endroit adéquat. Le docteur Alexandra Daruich, chirurgienne ophtalmologiste et chercheuse à l'Inserm revient sur le geste technique qu'elle pratique sur les enfants : Malheureusement, la thérapie génique ne permet pas de rendre la vision aux enfants. Elle vise surtout à stopper la maladie le plus tôt possible afin de limiter au maximum la dégénérescence. Néanmoins, il est arrivé, explique le professeur Matthieu Robert, que l'on constate une bonne surprise : En tout, l'hôpital Necker a effectué 11 opérations, chez six patients. La dernière est toute récente, sourit le docteur Alexandra Daruich : Pour l'ensemble des patients opérés pour l'instant, la vision est demeurée stable bien après l'opération et il n'y a pas eu de complications pendant ni après la chirurgie. La technique est donc très prometteuse. Guérir la drépanocytose, une maladie particulièrement douloureuse La drépanocytose est la plus fréquente des maladies rares. C'est une maladie du sang, qui touche au moins 300 000 personnes chaque année dans le monde. En France, on estime qu'un bébé sur 1 736 est porteur de cette maladie, selon les chiffres rapportés par l'Inserm en 2015. La drépanocytose est apparue en Afrique et en Asie puis elle s'est répandue ensuite en raison des mouvements de population. Elle est désormais présente aux Antilles, au Brésil et en Europe de l'Ouest. Cette maladie est particulièrement douloureuse puisqu'elle consiste en une déformation des globules rouges qui, moins souples, ne parviennent plus à passer facilement à travers tout le réseau veineux. La professeure Marina Cavazzana, p

NAMIJENJENO ISKLJUČIVO ZDRAVSTVENIM DJELATNICIMA. PRISTUPOM PODCASTU POTVRĐUJETE DA STE ZDRAVSTVENI DJELATNIK.PREDAVAČ:Prof.dr.sc. MILKA MAVIJA, dr.med. specijalista oftalmologijeŠef Klinike za očne bolestiUKC RS BanjalukaBanjaluka, BiHLINK NA TEČAJ Pristupom na CME aktivnost na Portalu CME.ba imate priliku da na kraju iste uradite završni test, te da dobijete akreditovani CME certifikat.Nasljedne bolesti retine su do prije par godina redovito završavale sa drastičnim oštećenjem vida i sljepilom u ranom životnom dobu. Terapijske mogućnosti su bile nikakve, sa praktično svezanim rukama za bilo kakav izgledniji pristup liječenju osim konstatacije progresivnog pogoršanja vida i sljepila.Međutim, paradigma se mijenja i u ovm polju napretkom modernih terapijskih pristupa od kojih je obećavajući upravo onaj o kome se govori u ovom izvanrednom revijalnom predavanju nacionalnog eksperta za oftalmologiju. Radi se, naime, o genskoj terapiji – pristupom gdje se uz pomoć virusnih vektora u oštećeni genom ćelija oka dostavljaju genetske informacije pomoću kojih se obnavlja produkcija proteina neophodnih za ispravnu funkciju.Voretigen neparvovek je jedan od takvih obećavajućih terapeutika, baziran na adeno-asociranom virusnom vektoru, a koji omogućava restituciju sinteze humanog RPE65, čime se stvara mogućnost obnove vidnog ciklusa. Izuzetno zanimljivo predavanje koje svakako preporučujemo za Vašu pažnju.Aktivnost je preporučena za specijaliste i specijalizante oftalmologije, a primjerena je i za studente medicine. Ova CME aktivnost je besplatna za registrirane članove. Registracija je također, besplatna.Tečaj je akreditovan od strane Ljekarske komore Tuzlanskog kantona.----------Ukoliko želite postati partner portala CME.ba ili želite da se Vaš brand ili audio poruke pojave na našim podcastima, mollimo da se javite na email info@cme.ba. Više informacija za potencijalne partnere potražite na OVOM LINKU.NOVARTIS Pharma, Predstavništvo Sarajevo At Novartis, we are reimagining medicine.

Hola y bienvenidos a un nuevo episodio de Canal Retina. Hoy tenemos un episodio muy especial ya que vamos a hablar con Noa Sola y con su mamá, Ana García. Para los que no los sepáis, os comentamos que Noa es la primera niña en ser intervenida en España de una distrofia hereditaria de retina, concretamente la amaurosis congénita de Leber con el gen RPE65 y fue operada en el hospital. Visítanos: https://canalretina.org/ https://www.retimur.org/

Retina UK Research Development Manager Kate Arkell speaks to three of the first people to receive the Luxturna (voretigene neparvovec) treatment in the UK. Jake, Lee and Matt all received the Luxturna gene therapy at the start of 2020. They all have two faulty copies of the RPE65 gene and are living with Leber congenital amaurosis type 2 (LCA2) and severe early-onset RP.

Dr. Daniel Chung is the global medical strategy lead for ophthalmology at Spark Therapeutics. Spark Therapeutics concentrates on discovering, developing, and delivering gene therapy for rare diseases. Dan works in the area of ophthalmology, and he and his colleagues brought the first FDA-approved gene therapy for a genetic disease to market. This therapy was created to treat an inherited retinal disease that results in blindness and is caused by variants or mutations in the RPE65 gene. When he isn’t working or traveling, Dan enjoys spending time with his family. He is also an avid photographer who loves capturing photos of nature, landscapes, and wildlife. In particular, he has really enjoyed photographing the panoramic landscapes of Monument Valley in Arizona, brown bears in Alaska, and polar bears in Northern Canada. Dan earned both his bachelor’s degree in biology and master’s degree in family counseling from Eastern Nazarene College in Massachusetts. He also holds a doctorate degree in Osteopathic Medicine (D.O.) from the New York College of Osteopathic Medicine. Afterward, Dan became a research training award fellow at the National Eye Institute of the National Institutes of Health, studying retinal gene therapy, and he went on to complete his residency in ophthalmology within the Summa Health System in Ohio. Dan joined the Cleveland Clinic as a pediatric ophthalmology clinical/ocular genetics research fellow and subsequently worked as a senior investigator at the Scheie Eye Institute in the Perelman School of Medicine at the University of Pennsylvania for eleven years before joining the team at Spark Therapeutics in 2014. In this interview, Dan shares more about his personal and professional passions, as well as his research.

Host: Jennifer Caudle, DO Guest: Jean Bennett, MD, PhD Guest: Albert Maguire, MD Power couple Drs. Jean Bennett and Albert Maguire discuss how their new therapy for the RPE65 gene, which causes retinal blindness, was recently approved by the FDA to become the first gene therapy treatment for a genetic disease in the United States and the first worldwide treatment for inherited blindness. Not only do they delve into the mechanics of the corrected gene injection, but they also explain what this milestone means for patient eligibility and how their marriage has played a role in the success of their research partnership. Dr. Jean Bennett is the F.M. Kirby Professor of Ophthalmology at the Perelman School of Medicine at the University of Pennsylvania, and Dr. Albert Maguire is a Professor of Ophthalmology at the Hospital of the University of Pennsylvania and Attending Physician in the Division of Pediatric Ophthalmology at Children's Hospital of Philadelphia.

Host: Jennifer Caudle, DO Guest: Jean Bennett, MD, PhD Guest: Albert Maguire, MD Power couple Drs. Jean Bennett and Albert Maguire discuss how their new therapy for the RPE65 gene, which causes retinal blindness, was recently approved by the FDA to become the first gene therapy treatment for a genetic disease in the United States and the first worldwide treatment for inherited blindness. Not only do they delve into the mechanics of the corrected gene injection, but they also explain what this milestone means for patient eligibility and how their marriage has played a role in the success of their research partnership. Dr. Jean Bennett is the F.M. Kirby Professor of Ophthalmology at the Perelman School of Medicine at the University of Pennsylvania, and Dr. Albert Maguire is a Professor of Ophthalmology at the Hospital of the University of Pennsylvania and Attending Physician in the Division of Pediatric Ophthalmology at Children’s Hospital of Philadelphia.

Host: Jennifer Caudle, DO Guest: Jean Bennett, MD, PhD Guest: Albert Maguire, MD Power couple Drs. Jean Bennett and Albert Maguire discuss how their new therapy for the RPE65 gene, which causes retinal blindness, was recently approved by the FDA to become the first gene therapy treatment for a genetic disease in the United States and the first worldwide treatment for inherited blindness. Not only do they delve into the mechanics of the corrected gene injection, but they also explain what this milestone means for patient eligibility and how their marriage has played a role in the success of their research partnership. Dr. Jean Bennett is the F.M. Kirby Professor of Ophthalmology at the Perelman School of Medicine at the University of Pennsylvania, and Dr. Albert Maguire is a Professor of Ophthalmology at the Hospital of the University of Pennsylvania and Attending Physician in the Division of Pediatric Ophthalmology at Children’s Hospital of Philadelphia.

Host: Jennifer Caudle, DO Guest: Jean Bennett, MD, PhD Guest: Albert Maguire, MD Power couple Drs. Jean Bennett and Albert Maguire discuss how their new therapy for the RPE65 gene, which causes retinal blindness, was recently approved by the FDA to become the first gene therapy treatment for a genetic disease in the United States and the first worldwide treatment for inherited blindness. Not only do they delve into the mechanics of the corrected gene injection, but they also explain what this milestone means for patient eligibility and how their marriage has played a role in the success of their research partnership. Dr. Jean Bennett is the F.M. Kirby Professor of Ophthalmology at the Perelman School of Medicine at the University of Pennsylvania, and Dr. Albert Maguire is a Professor of Ophthalmology at the Hospital of the University of Pennsylvania and Attending Physician in the Division of Pediatric Ophthalmology at Children’s Hospital of Philadelphia.

Hear the story of the first gene therapy approved in the United States to target a disease caused by mutations in a specific gene. In this case, the RPE65 gene, which affects vision. For Dr. Jean Bennett, the physician scientist behind this medical breakthrough, being able to change the prognosis for people who are blind or losing their vision — and to see the profound impact that this has on their life — has been a career well spent.

Christian Guardino is a 17-year-old singer who competed last year on America’s Got Talent and made it to the semifinals. Christian was diagnosed with Leber congenital amaurosis (LCA) as an infant, and his vision continually declined as he got older. At 13, he entered the RPE65 gene therapy clinical trial being conducted by the Children’s Hospital of Philadelphia and Spark Therapeutics. Since then, Christian has enjoyed a 75–80 percent improvement in his vision. Currently, Christian is serving as a Champion for Children’s Miracle Network Hospitals.   Listen to this episode and learn: What it was like growing up with limited eyesight How facebook helped Christian’s mother find the answer to a cure for his disease Christian’s advice for others going through a difficult time How Christian fulfilled his dream of performing in front of Simon Cowell. What is was like work with Grammy award winning songwriter Sacha Skarbvek and American Idol winner Jordin Sparks

Dr. Stephen Russell discusses his group's recent publication in Lancet (http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31868-8/fulltext) regarding successful phase 3 trial results of viral vector RPE65 gene therapy, the first such successful trial in medicine.

Bellus Health is left reeling as its lead drug Kiacta fails its Phase 3 clinical study, Vancouver based QLT inks a merger deal with Aegerion Pharmaceuticals and looks to a fresh new start, and Biotechnology Focus relaunches its Hot Button Issue Survey. We have this and more on this weeks show! Show Notes: We kick things off this week with some bad news on both the business and the clinical trial front with BELLUS Health the rare disease drug development firm reporting top line results from its Phase 3 study of KIACTA™ (eprodisate) as a treatment of AA amyloidosis. The disease is characterized by secondary to severe chronic inflammation or infection leading to the formation and deposition of amyloid fibrils in organs, often resulting in end-stage renal disease and death. Currently there are no therapies available that target the disease directly. According to company CEO Roberto Bellini, KIACTA™ failed to meet its primary efficacy endpoint in slowing renal function decline. The news, announced on June 20, was somewhat surprising to both the company and its investors. Shares for the company on the TSE under the trade symbol BLU plummeted, going from $2.42 on June 17, to around $0.39 on the day of the announcement, holding at .40 cents today. Many investors had rallied to the company over the past year due to the drug being in later stages of clinical trial development. Moreover, the science seemed sound as in earlier studies, KIACTA™ was shown to significantly delay the disease.  In both earlier studies and even in the failed trial, it was found to be safe and well tolerated over treatment periods of greater than four years. The confirmatory Phase 3 study of KIACTA™ was a global study across more than 70 sites in more than 25 countries that randomized 261 patients to receive either 800mg dose of KIACTA™ twice daily or placebo. The  study was an event driven study that lasted five years meeting its completion target of 120 patient events linked to the deterioration of kidney function in January 2016. The company added that further analysis of the data is ongoing, and a more detailed data set of the KIACTA™ Phase 3 study will be presented July 6 at the XV International Symposium . Roberto Bellini, president and CEO of the company adds that while Bellus is disappointed that the Phase 3 study did not meet the primary efficacy endpoint, the full data set will be assessed to determine the best path forward. The company says in the aftermath of the failed trial, it will continue working on a number of other projects in its portfolio,  including its study of KIACTA™ as a treatment for sarcoidosis (set to enter Phase 2 trials), clinical development of Shigamab™ as a treatment for STEC-related Hemolytic Uremic Syndrome (sHUS), and the company’s research-stage project for AL amyloidosis. We go from negative news to the more positive, as QLT Inc., once upon a time Canada’s hottest biotech company, and a company long-entrenched as a in the BC- biotech community inking a strategic merger agreement with Cambridge-based Aegerion Pharmaceuticals, Inc. The proposed deal has been approved by the board of directors of both companies, and is expected to close late in the third quarter or during the fourth quarter of 2016. Upon closing, QLT says it plans to change its name to Novelion Therapeutics Inc. adding that its common shares will trade on the NASDAQ Global Select Market and the Toronto Stock Exchange. QLT’s current market cap is approximately $110 million (CDN) and Aegerion has a market cap of approximately $70 million (CDN) giving the new combined company a market value of approximately $180 million. This isn’t QLT’s first attempt to merge with another company, having been thwarted in the past in prior merger arrangements with Endo International, Auxilium Pharmaceuticals and InSite Vision. The planned merger with Endo International was terminated in October 2014, and likewise, Auxilium had also been carrying out plans to merge with QLT but chose instead to be bought by the aforementioned Endo International in a separate deal valued at $2.6 billion. Likewise, last year, QLT and InSite announced a merger, but that deal fell through after InSite changed its mind and accepted a higher merger offer from Sun Pharmaceutical Industries. This time QLT won’t be left at the alter so to speak, and likewise both companies under the Novelion Therapeutics Inc. banner will get a much needed rebrand and fresh start. The new company will also have quite a diversified portfolio consisting of Aegerion’s two commercially branded products, Juxtapid® (lomitapide) capsules and Myalept® (metreleptin), and QLT’s QLT091001 (Zuretinol Acetate or Zuretinol), a Phase 3-ready Ultra-Orphan Fast Track and Orphan Drug designated asset being developed for the treatment of Inherited Retinal Disease caused by underlying mutations in RPE65 or LRAT genes (IRD), which indication comprises Leber Congenital Amaurosis (LCA) and Retinitis Pigmentosa (RP). Aegerion’s CEO, Mary Szela, will serve as CEO of Novelion following the close of the transaction. Additionally, an investor syndicate comprised of both new investors and existing shareholders of both companies has  committed to invest via a private placement approximately $22 million in QLT. The investment will be funded prior to the transaction close and is expected to provide Novelion with additional capital to support future operations and the potential opportunity for targeted business development initiatives. In futher business news, TVM Life Science Ventures VII a venture capital fund domiciled in Montréal, Québec, has closed the fund’s eleventh investment, establishing Mediti Pharma Inc., a company based in Montréal, Québec. The new company is developing a Phase 2 ready compound, MP-101, originally discovered by Eli Lilly and Company for the treatment of Alzheimer’s disease (AD) psychosis. The behavioral symptoms associated with AD psychosis, include hallucinations, delusions and aggression. The company is managed by CEO Dr. Ivan Shaw, formerly with Merck Frosst, Aptalis and Actavis and neurobiologist and experienced drug developer and CFO Mark Cipriano, a Boston-based highly experienced and networked executive. As for the fund itself, and its initial association with the drug, it comes about as part of a unique arrangement between TVM Capital Life Science and numerous limited partners, which includes Eli Lilly and Company.  The goal of the fund is to finance and access innovation while managing risk and sharing reward. Staying in Montreal, on the clinical trial front Montreal InVivo , the city’s economic development organization with a focus on life sciences and health technologies (LSHT) sector. is partnering with Canadian Clinical Trails Coordinating Centre(CCTCC) to enhance Canada's clinical research capabilities. The partnership will result in the addition of Quebec clinical trial investigators "data from Montreal Goes Clinic to the Canadian ClinicalTrials Asset Map (CCTAM) and real-time updates down the line. The Montreal Goes Clinic itself is an initiative by Greater Montreal's life sciences"; cluster that aims to make the region a world-class centre of expertise in early stage clinical trials.  The goal of this initiative is to improve Greater Montreal's business environment by helping pharmaceutical, biotech, contract research organizations (CRO's) and medical device companies perform high quality clinical trials and run clinical proofs-of- concept, thus  increasing patient access to new treatments and improving medical practices by allowing clinicians to work with technologies of tomorrow and the best equipment. Frank Béraud, CEO of Montréal InVivo adds that the portal will create more visibility for Quebec's researchers and investigators throughout Canada, and will also showcase the province's capabilities in clinical research. Dr. Shurjeel Choudhri, senior vice president and head, Medical and Scientific Affairs Bayer Inc. and the current Chair of the CCTCC Executive Committee adds that the CCTAM is a great example of the collaboration of multiple stakeholders from across Canada, including representatives from the Federal and Provincial governments, industry, the Canadian Institutes of Health Research and HealthCareCAN. He calls the addition of clinical investigator data from Montreal Goes Clinic an important step towards making the CCTAM a truly comprehensive inventory of Canada's clinical research assets. If you could have a face-to- face conversation with government to discuss the life science industry, both the good and the bad what would you say? A number of years ago Biotechnology Focus used to run a special Hot Button Issue survey which gave our readers the opportunity to engage with government to get their concerns before the right people and have their voices heard. Well, with the Justin Trudeau government coming up to its ninth month in office, we thought the timing was right to do it all again. The survey kicked off yesterday and will run to July 15, 2016. Similar to our past “Hot Button” issue surveys, we want your feedback on such things as regulatory policy including reimbursement of new technologies, funding challenges, intellectual property protection, the state of the industry and much more. This survey is open to everyone in the industry, from the business sector, to research institutions, and at all levels, essentially, if your field is biotech, bioscience or life science in general we want to hear from you. This already is vibrant industry, with strong representation at major research and knowledge translation institutions, a large base of Canadian biotech SMEs and MMEs, and we’re home to many of the world's largest and leading pharmaceutical companies. Moreover, the timing for this survey couldn’t be better as the Federal government as mentioned in last week’s podcast has just launched the “Innovation Agenda”, an action plan to both redesign and redefine how we as a nation support innovation and growth. They have embarked on this Innovation Agenda in partnership and coordination with the private sector; provinces, territories and municipalities; universities and colleges; and the not for-profit sector and they have also already taken the first steps in this plan already with Budget 2016, providing support for health research, genomics, regenerative medicine, brain research and drug development and committed $800 million to support innovation networks and clusters. So there’s obviously lots that government is doing right to make Canada a friendly environment for our industry, but can we do more? Canada’s Minister of Innovation, Science and Economic Development Navdeep Bains has asked us all to step up and voice our opinions, to help further shape the future of Canada’s knowledge based economy. And our Hot Button Issue survey is your chance to do that! Your answers will be featured in a special high profile issue that will be poly-bagged with our sister publication Canadian Government Executive magazine and sent to Deputy Ministers, Assistant Deputy Ministers, Cabinet, Directors and Generals, working in Health Canada, Industry Canada, Agriculture & Agri-Food, Foreign Affairs & Internationals trade, the Privy Council as well as other public sector executives in federal and provincial departments. So here is your chance to help influence the Innovation Agenda. And remember, by taking only a couple of minutes to complete our survey, you’re helping us grow Canada’s knowledge-based economy, one answer at a time. You can access the survey by clicking the link below this podcast. That wraps up this weeks show, you can find us online at www.biotechnologyfocus.ca. Likewise, we’re always looking for feedback, story ideas and suggestions so we’d love to hear from you. Simply reach out to us on twitter: @BiotechFocus , email at biotechnology_focus@promotive.net For all of us here at Biotechnology Focus, thank you for listening.

Jeffrey D. Marrazzo, Co-Founder and CEO of Spark Therapeutics, discusses the successful Phase III trial of its lead candidate, SPK-RPE65, was able to improve functional vision in patients with a rare form of a genetic disorder known as RPE65-mediated inherited retinal dystrophies. SPK-RPE65 is intended to treat rare blinding conditions caused by mutations in the RPE65 gene, which is linked to subtypes of Leber congenital amaurosis (LCA type 2) and retinitis pigmentosa (RP type 20). Wall St. approved as well--Spark shares rose almost 60% to $70 in trading before the market opened the day of the announcement. The study results represent the first successful randomized, controlled Phase 3 trial ever completed in gene therapy for a genetic disease, Spark executives said.

Die equine rezidivierende Uveitis (ERU) ist eine sehr häufig auftretende autoimmune Augenerkrankung bei Pferden, welche meist mit dem Verlust der Sehfähigkeit der betroffenen Augen einhergeht. Da die ERU das einzig spontane Tiermodell für die humane autoimmune Uveitis darstellt, ist die Erforschung der zugrundeliegenden Pathomechanismen der ERU nicht nur veterinärmedizinisch, sondern auch für die Humanmedizin von großer Bedeutung. Charakteristisch für die ERU sind der Zusammenbruch der Blut-Retina-Schranke (BRS) und die Infiltration von autoaggressiven T-Lymphozyten in das innere Auge mit anschließender Zerstörung retinaler Strukturen. Beim Pferd wird die BRS, aufgrund der weitestgehend avaskulären Retina, hauptsächlich von der äußeren Komponente der BRS gebildet, dem retinalen Pigmentepithel (RPE). Im physiologischen Zustand stellt das RPE durch feste Zell-Zellverbindungen sowohl eine stabile mechanische, als auch durch seine Fähigkeit, mit Mediatoren des Immunsystems kommunizieren und interagieren zu können, eine effektive immunologische Barriere dar. Die im Verlauf der ERU stattfindenden pathophysiologischen Mechanismen, welche für den Zusammenbruch dieser Barriere verantwortlich sind, konnten bislang nicht ausreichend geklärt werden. Vor allem Änderungen im Expressionsmuster des Zelloberflächenproteoms könnten hierbei aufgrund der ständigen Interaktion und Kommunikation der RPE-Zellen mit ihrer Umgebung eine entscheidende Rolle spielen. Deshalb war es das Ziel dieser Arbeit, differentiell regulierte Zelloberflächen-proteine zwischen gesunden und uveitischen RPE-Zellen zu detektieren, welche maßgeblich an der Pathogenese der ERU beteiligt sein könnten. Um so nah wie möglich die am RPE in vivo stattfindenden physiologischen und pathophysiologischen Prozesse widerspiegeln zu können, wurden RPE-Zelloberflächenproteine von gesunden und an ERU erkrankten Pferden in dieser Studie mittels einer neuartigen in situ Biotinylierungsmethode angereichert und anschließend massenspektrometrisch analysiert. Dabei konnten insgesamt 148 Proteine identifiziert werden, von denen 81,8 % Plasmamembranproteine waren, was deutlich für den Erfolg der neuartigen Anreicherungsmethode sprach. Unter den 148 insgesamt identifizierten Proteinen befanden sich 27 differentiell regulierte Proteine, wovon in uveitischem RPE drei hoch- und 24 herunterreguliert waren. Neben den für RPE-Zellen klassischen Proteinen wie RPE65, Rhodopsin und S-Arrestin konnten auch mehrere Proteine detektiert werden, die unseres Wissens zuvor noch nicht in RPE-Zellen beschrieben wurden, wie der Glukosetransporter 4, Synaptotagmin 1 und Peripherin 2. Funktionell besonders interessant fanden wir die vier Proteine Synaptotagmin 1, Basigin, Collectrin und Perpherin 2, welche alle mit einer verminderten Expression in uveitischem RPE zu finden waren. Interessanterweise ergab sich aus einer Pathway-Analyse für alle vier Proteine eine Beteiligung an „Visual Functions“ und „Immunological Diseases“. Mittels weiterführender Analysen wie der Durchflusszytometrie, der Immunhistologie und der Quantifizierung der Protein-Fluoreszenzintensitäten ist es gelungen die bereits massenspektrometrisch identifizierte verminderte Expression von Synaptotagmin 1, Basigin, Collectrin und Perpherin 2 zu verifizieren und die Proteine näher zu charakterisieren. Die in dieser Arbeit präsentierte neuartige in situ Biotinylierungsmethode zur Anreicherung von Oberflächenproteinen, welche anschließend mittels LC-MS/MS identifiziert wurden, erwies sich als sehr effektive und innovative Methode, um Oberflächenproteine so nah wie möglich in ihrem physiologischen und pathophysiologischen in vivo Vorkommen zu untersuchen. Daher liefert der in dieser Arbeit generierte Datensatz der differentiell regulierten Proteine zwischen gesunden und uveitischen RPE-Zellen eine solide Grundlage für weitere funktionelle Analysen zur Aufklärung der Pathogenese der ERU.

Interview with Samuel G. Jacobson, MD, PhD, author of Gene Therapy for Leber Congenital Amaurosis Caused by RPE65 Mutations: Safety and Efficacy in 15 Children and Adults Followed Up to 3 Years