WWW.DISSERTATION.XLIBX.INFO
FREE ELECTRONIC LIBRARY - Dissertations, online materials
 
<< HOME
CONTACTS



Pages:   || 2 | 3 | 4 |

«Abstract Modern medicine development is alike unlocking mystery of black box. The journey of 10- year drug development is about establishing a drug ...»

-- [ Page 1 ] --

OPHTHALMOLOGY

Cronicon OPEN ACCESS

Review Article

New Frontiers of Retinal Therapeutic Innovation & Strategic Insights

Tina Guanting Qiu* (review by Alan M Laties, MD)1

Department of Ophthalmology, University of Pennsylvania, USA

*Corresponding Author: Tina Guanting Qiu, MD PhD, Biopharma Physician & Executive Consultant, 3212 Crane Brook Way, Peabody MA 01960 USA.

Received: August 16, 2015; Published: September 05, 2015 Abstract Modern medicine development is alike unlocking mystery of black box. The journey of 10- year drug development is about establishing a drug molecular biological trait along with its pharmacological behaviors in animal disease models and various human conditions. Product medical strategy has become ever more important in bridging gaps for translational efficiency. This review focuses on the paradigm shift of therapeutic intervention for retinal diseases. Topics include: 1) Emerging ocular drug delivery innovation from polymer-based sustained-release drug delivery to genetic engineering protein biofactory (superachoroidal and subretinal routes begin to merge). 2) New themes of tissue rejuvenation and parainflammation in retina and glaucoma disease management. 3) New highs in disease alteration by emerging therapies - the switch from “wet to dry” vascular AMD (age-related macular degeneration) is a great example of such in the new era of anti-VEGF therapy. 4) Bio-therapeutic innovation at a glance. 5) Understand disease staging and phenotype stratification is “A Must” in developing personalized treatment algorithm. New evidences suggest that AMD represents a group of heterogeneous clinical pathological entity that includes RPE aging, photoreceptor loss, Bruch’s membrane thickening, and choroid ischemia, among which one or more can be the primary trigger and predominant clinical phenotype. New appreciation of glaucoma as a neural degenerative disease involving pressure-dependent and pressure-independent risk factors may lead to breakthrough of neural protection drug development in the 21st century. In summary, reduce photoreceptor and retinal ganglion cell loss is the ultimate goal of therapeutic intervention for a large spectrum of significant neurovascular diseases in the retina.

(254 words).

Keywords: Glaucoma; Parainflammation; Photoreceptor; Retina; Eye; Rejuvenation In the retina, there are two biggest problems spanning at two extreme ends. One end is about cell proliferation such as choroid neoIntroduction vascularization (CNV), proliferative vitraretinopathy (PVR), proliferative diabetic retinopathy (PDR), epiretinal or subretinal fibrosis and scar formation, as well as inflammatory cell proliferation. The other end is abnormal cell loss due to apoptotic and necrotic cell death in various genetic or acquired pathological conditions, such as age-related macular degeneration (AMD), glaucomatous neural degeneration, retinitis pigmentosa (RP) and Stargardt’s macular degeneration (SMD), for which regenerative medicine comes into a play. In the past two decades, scientific advances have allowed us to gain in-depth understanding of molecular pathophysiological mechanisms involved retinal diseases, which are changing the way of how we treat patient and how we project future medicine.

This review covers both clinical development and cutting edge technologies with new themes on basement membrane rejuvenation and parainflammation along with some of the most exciting happenings in retina and glaucoma disease management for the back of the eye. In the light of retina therapeutic area: 1)The appreciation of dry AMD clinical sub-phenotypes is paving the way of precision medicine development for early stage AMD clinical trials (e.g. patient enrollment). 2) Long-term anti-VEGF therapy is altering vascular AMD nature course with a switch from wet to dry clinical phenotype. 3) New minimally invasive sustained-release ocular drug delivery along with

Citation: Tina Guanting Qiu. “New Frontiers of Retinal Therapeutic Innovation & Strategic Insights”. EC Ophthalmology 2.2 (2015):

81-91.

New Frontiers of Retinal Therapeutic Intervention & Product Development Strategy (Review) novel genetic and RNA based protein bio-factories are ophthalmic innovation frontiers. In glaucoma, the disease management has shifted its paradigm from simple IOP reduction towards long-term IOP stability and neural protection through modulating non-IOP dependent risk factors. On surgical front, micro-invasive glaucoma surgery (MIGS) plus Phaco cataract removal are offering new alternatives for early stage glaucoma treatment algorithm. Additionally, as we know macula is in charge of the most precious vision in our life. A rising wave of low dose steroid sustained delivery for refractory diabetic macula edema (DME) is deepening our understanding about the disease pathological entities, which are not a simple VEGF caused vascular disease but involve significant chronic parainflammation. Finally the game ends with severe retinal ganglion cell (RGC) and photoreceptor cell loss. So far, the only solution is replacement via either artificial retinal prosthesis (e.g. bionic eye) or stem cell regenerative medicine.

1. New Advances in Age-related Macular Degeneration (AMD) AMD is the leading cause of irreversible visual devastating disease in western country in age over 65-year old. In textbook, drusen 1.1: AMD Clinical Sub-phenotypes and Root Causes is the hallmark of dry AMD. Well, what if patient does not have drusen, does he/she have AMD? Recent studies have demonstrated that there are 4 predominant subclinical phenotypes associated with early stage AMD, among which one or two more could be the predominant driven forces for disease pathological progress towards advanced stage [1,2]. These four pathological clinical sub-phenotypes are





1) Retina pigment epithelium (RPE) atrophy due to aging. 2) Photoreceptor (cone) loss can be a primary trigger. 3) Bruch’s membrane aging is the rate limit pathological process for AMD (Prof. John Marshall). 4) Choroid ischemia (capillary patchy loss) is a hidden devil that is beginning to receive attention (Prof. Alan Bird). Finally parainflammation and complement pathway are the new themes for therapeutic targets on dry AMD.

With the huge success of anti-VEGF therapy for wet AMD, treatment paradigm has shifted toward pathway-based therapeutic strategy to addressing various root causes associated with early stage dry AMD. Figure 1 depicts a road map of these baby-boomer early phase clinical trials, among which anti-complement factor D (lampalizumab) via intravitreal injection perhaps is the front-runner at Phase 3 showing a promise in preventing geographic atrophy (GA) and vision deterioration in patients with dry AMD [3]. Retina rejuvenation therapy (2RT) is a rising star being developed by Ellex for the treatment of drusen in dry AMD, which has showed encouraging clinical results on the clearance of patchy or dotty drusen in phase 2 clinical trials [4].

Since the first pathway-based anti-VEGF therapy Lucentis was brought to market back to 2002, emerging anti-VEGF drugs including 1.2: Effects of Long-term Anti-VEGF Therapies on Wet AMD Elyea and Avastin (off label) have revolutionized pharmacotherapy for vascular retina diseases including subretinal choroidal neovascularization (CNV). Yet there are two rising problems associated with long-term anti-VEGF treatment. According to Seven-Up study report in 2013, after 3 years Lucentis treatment, one-third of the treated patients may gradually lose their vision due to subretinal fibrosis or scar formation, or increased geographic atrophy [5]. These late stage subretinal CNV lesions often contain complex cellular components such as macrophage and microglia infiltrations, Muller glia cell remodeling, and fibroblast proliferation. As of result, the CNV pathological entity may evolve from early stage VEGF-driven microcapillary lesion towards late stage arteriolarized new vascular lesion. Thus, they do not respond well to anti-VEGF treatment. Ophthotech (NY) is pioneering 3rd generation wet AMD therapeutic strategy with a clinical phase 3 target, anti-platelet-derived growth factor (anti-PDGF) called Fovista in combination with Lucentis to address this rising pandemic fibrotic problem, which has showed significant efficacy and favorable safety [6]. Another phenomenon is the switch from wet to dry clinical phenotype. According to the CATT study group report in 2014, anti-VEGF treatment may drive the “wet” CNV lesion converging into advanced geographic atrophy (GA) with increased and well-demarcated RPE atrophy, which is similar to de novo dry AMD [7]. Ocata Therapeutic (MA) is pioneering the first human embryonic stem cell derived RPE transplant to address such significant RPE loss in various advanced macular degenerative diseases, including dry AMD, SMD, and myopic macular degeneration. They are at phase 2b clinical development with encouraging future prospect [8].

Citation: Tina Guanting Qiu. “New Frontiers of Retinal Therapeutic Innovation & Strategic Insights”. EC Ophthalmology 2.2 (2015):

81-91.

New Frontiers of Retinal Therapeutic Intervention & Product Development Strategy (Review)

–  –  –

2. New Horizons on Glaucoma Disease Management “In glaucoma clinic, some patients, no matter how you treat them, they still go blind” cited from Dr. Kuldev Singh, President of AmerIOP dependent and non-IOP dependent risk factors ica Glaucoma Society-2012. This entails a truth that IOP independent factors play important roles in glaucomatous neural degeneration.

Therefore, current standard of care by reducing IOP alone suffers a great limitation. Normal tension glaucoma (NTG) is a classic example that multiple vascular and intricate inflammatory components (ET-1, TNFa, NF-Kappa) other than elevated intraocular pressure alone are responsible for the sneaky vision loss in this subset disease category [9]. The Figure 2 highlights different cellular compartments (e.g. mitochondria, microglia), key pathological signaling pathways (ischemia-reperfusion damage, NF-kappa B based parainflammatory pathways) and multiple causative factors (glutamate, calcium influx, TNF-a, beta amyloid, beta crystalline), which are contributing to RGC death in glaucoma disease pathological progress. Among these causative factors, neurovascular imbalance and parainflammation have received great interests in both academic and industry, which indicates a strategic importance for drug discovery and development for glaucoma patient care.

Neural protection has been century dogma. The 20th century has been an era of neurotrophin (NT) based interventional approach 2.2: A New Prospect of Neural Protection for Glaucoma/Retina via tyrosine kinase signals for both central nervous system (CNS) and retina degenerative disorders. A cluster of neurotrophic growth factors, such as NGF (neural growth factor), BDNF (brain-derived neurotrophic factors), CNTF (ciliary neurotrophic factor), NT 3, and NT 4/5 have been exhaustively studied and tested in various preclinical disease models and early stage clinical trials in patients with RP and AMD. So far, there has not been any success yet. Looking forward in the 21st century, we believe that preventing neuronal cell death (neural protection) has to be proactive either through regenerative approach or directly addressing the fundamental root causes underlying cell apoptosis or necrosis. Currently there are three new class small molecules being evaluated for their potentials to rescue retinal ganglion cell and/or photoreceptor death in glaucoma and various retinal conditions. Trabodenoson (Inotek Pharma) is a new class of adenosine mimetic highly selective to A1 receptor (A1R), which is being developed for glaucoma IOP management with additional evidence of rescuing RGC from ischemia-reperfusion damage in preclinical rat model. Unoprostone isopropyl (rescula, 0.12% eye drops) is a newly discovered B-K channel activator with great advantage of pre-existing market experience since 1994 [10]. Currently the same formulation is being tested in Phase 3 clinical trials for RP in Japan (R-Tech Ueno) [11]. Based on author’s recent investigation and

Citation: Tina Guanting Qiu. “New Frontiers of Retinal Therapeutic Innovation & Strategic Insights”. EC Ophthalmology 2.2 (2015):

81-91.

New Frontiers of Retinal Therapeutic Intervention & Product Development Strategy (Review) understanding about B-K channel activation, unoprostone may have broad pharmacological and therapeutic implications in modulating neurovascular imbalance, choroid ischemia and parainflammation in certain subset clinical phenotypes. Similar to rescula, Brimonidine (0.2% or 0.25%) is also a very old ocular hypotensive drug, which is being repositioned through sustained release intravitreal implant for its neural protective potentials in various retinal abnormalities (Allergan) [12]. Of important note, Brimonidine is vascular constrictive, which may contradict with disease pathological process involved with choroid ischemia and neurovascular problems, such as AMD and NTG. Perhaps this might explain why recent Phase 2 clinical trials on dry AMD, RP, glaucomatous neuropathy and macular-off retinal detachment have not achieved satisfaction yet [13].

–  –  –

The concept of regenerative medicine has gone beyond tissue organ transplant. For example, the “tales” of basement membrane



Pages:   || 2 | 3 | 4 |


Similar works:

«Biographical Sketch CURRICULUM VITAE Name: Guy H. Loneragan Title: Professor of Food Safety and Public Health, and Faculty Fellow Address: Texas Tech Univ., MS 42141, Lubbock, Texas 79409-2141 Telephone: (806)834-1291 Fax: () E-mail: Guy.Loneragan@ttu.edu A. Education/Training YEAR INSTITUTION AND LOCATION DEGREE FIELD OF STUDY (s) 1999Colorado State University, Ft. Collins, CO PhD Epidemiology 2001 1996Population and Colorado State University, Ft. Collins, CO MS 1998 production medicine...»

«Keeping Your Eyes Healthy Vision problems and eye conditions can affect people of all ages. That’s why it’s so important to take care of your eyes—starting early in life. The following tips can help you keep them safe and healthy: Don’t smoke. This dangerous habit deprives your body of nutrients that are essential in preventing certain eye diseases. If you smoke and need help quitting, talk with your doctor. Enjoy your fruits and veggies. Eat at least three to five servings of fruits...»

«Gordon Fisher, Ph.D. Assistant Professor The University of Alabama at Birmingham (UAB) Department of Human Studies EB Building 232J, 901 13th St. South Birmingham, AL 34294-1250 Voice: (205) 996-4114 Fax: (205) 934-7050 Email: grdnfs@uab.edu EDUCATION: University of Alabama at Birmingham, Birmingham, AL Postdoctoral Fellow, Department of Nutrition Sciences, June 2010-August 2012 Nutrition and Obesity Research Center Division of Physiology and Metabolism Auburn University, Auburn, AL Ph.D....»

«Maternal, Infant, and Young Child Nutrition in Malawi Community Nutrition Workers RECIPE BOOK Photos by Osborne Sibande D EC E M B E R 2011 This document was produced through support provided by the United States Agency for International Development, under the terms of Cooperative Agreement No. GPO-A-00-0600008-00. The opinions herein are those of the author(s) and do not necessarily reflect the views of the United States Agency for International Development. Table of contents Preface Part 1:...»

«Electrophysiological studies on visual information processing in dyslexia and ADHD Monica Dhar Paranimfs: Fiona Koster Roeljan Wiersema Financial support for the publication of this thesis was provided by the University of Groningen, the Graduate School of Behavioural and Cognitive Neurosciences, EASYCAP, and MedCat medical equipment and accessories. Printed in the Netherlands by Wöhrmann Print Service. © 2009 M. Dhar RIJKSUNIVERSITEIT GRONINGEN Electrophysiological studies on visual...»

«Gelfoam® absorbable gelatin compressed sponge, USP DESCRIPTION GELFOAM Sterile Compressed Sponge is a medical device intended for application to bleeding surfaces as a hemostatic. It is a water-insoluble, off-white, nonelastic, porous, pliable product prepared from purified porcine skin, Gelatin USP Granules and Water for Injection, USP. It may be cut without fraying and is able to absorb and hold within its interstices, many times its weight of blood and other fluids. ACTIONS GELFOAM Sterile...»

«J.-2. REPORT ON THE INDIGENOUS MEDICAL BOTANY OF MASSACHUSETTS. By STEPHEN W. WILLIAMS, M. D. PRELIMINARY REMARKS. The plants of Massachusetts have been pretty thoroughly investigated, by able botanists. Although the State embraces but a small extent of territory, and much of the soil is rocky and barren, and although she is situated in a pretty high northern latitude, for the temperate zone, she, nevertheless, has some as warm weather as is to be found in the sunny regions of the south, though...»

«International Review of the Red Cross (2014), 96 (894), 479–484. Sexual violence in armed conflict doi:10.1017/S1816383115000284 Q&A: ON SEXUAL VIOLENCE IN DETENTION Through the eyes of a detention doctor: Interview with Raed Aburabi* Dr Raed Aburabi has been working for the International Committee of the Red Cross (ICRC) for twenty years. He is currently in charge of the health in detention unit at the ICRC’s Headquarters in Geneva. As part of his work, he visits countries in which the...»

«Dose-Response, 8:534–542, 2010 Formerly Nonlinearity in Biology, Toxicology, and Medicine Copyright © 2010 University of Massachusetts ISSN: 1559-3258 DOI: 10.2203/dose-response.10-033.Blankenbecler LOW-DOSE PRETREATMENT FOR RADIATION THERAPY Richard Blankenbecler Professor emeritus, Stanford Linear Accelerator Center, Stanford University, Stanford CA; Adjunct Professor of Physics, Virginia Tech, Blacksburg VA; Adjunct Fellow, Nevada Cancer Institute, Las Vegas NV In radiotherapy, a large...»

«Open PHACTS Milestone 4 Core services released to broader community Prepared by Pfizer, CD, VUA, UNIVIE Approved by UNIVIE, GSK, VUA March 2013 Version 1.0 Project title: An open, integrated and sustainable chemistry, biology and pharmacology knowledge resource for drug discovery Instrument: IMI JU Contract no: 115191 Start date: 01 March 2011 Duration: 3 years Nature of the Deliverable x Report Prototype Other Dissemination level x Public dissemination level For internal use only © Copyright...»

«Meibomian Gland Dysfunction Lecture and interactive teaching Mr Teifi James DO FRCP FRCS FRCOphth. Consultant Ophthalmologist. Halifax and Elland, West Yorkshire Address for correspondence. The Eye Clinic. Calderdale Royal Hospital. Halifax. HX3 0PW email teifi@mac.com Meibomian Gland Dysfunction or MGD is often seen as a nuisance or an 'excuse diagnosis‟ for a troublesome patient. In truth, MGD is incredibly common and the more you look for it, the more often you find it. MGD is the common...»

«OULU 2012 D 1156 ACTA U N I V E R S I T AT I S O U L U E N S I S D MEDICA Annukka Hannula IMAGING STUDIES OF THE URINARY TRACT IN CHILDREN WITH ACUTE URINARY TRACT INFECTION UNIVERSITY OF OULU GRADUATE SCHOOL; UNIVERSITY OF OULU, FACULTY OF MEDICINE, INSTITUTE OF CLINICAL MEDICINE, DEPARTMENT OF PAEDIATRICS ACTA UNIVERSITATIS OULUENSIS D Medica 1156 ANNUKKA HANNULA IMAGING STUDIES OF THE URINARY TRACT IN CHILDREN WITH ACUTE URINARY TRACT INFECTION Academic dissertation to be presented with the...»





 
<<  HOME   |    CONTACTS
2016 www.dissertation.xlibx.info - Dissertations, online materials

Materials of this site are available for review, all rights belong to their respective owners.
If you do not agree with the fact that your material is placed on this site, please, email us, we will within 1-2 business days delete him.