Scientific Program

Conference Series Ltd invites all the participants across the globe to attend 4th International Conference on Clinical & Experimental Ophthalmology Baltimore, USA.

Day 3 :

  • Track 8: Ophthalmic Research & Drug Development
Location: Harbor Room
Speaker

Chair

Tao L. Lowe

University of Tennessee College of Pharmacy, USA

Speaker

Co-Chair

Ruiwen Shi

Allergan Inc., USA

Session Introduction

Tao L. Lowe

University of Tennessee College of Pharmacy, USA

Title: Craft materials to overcome ocular barriers

Time : 13:20-13:40

Speaker
Biography:

Tao Lowe is an Associate Professor of Pharmaceutical Sciences and Biomedical Engineering at University of Tennessee. Previously, she was an Assistant Professor of Surgery, Bioengineering, and Materials Science and Engineering, and Co-Director of the Integrated Graduate Degree Molecular Toxicology Program at Pennsylvania State University. She received her Ph.D. with an Eximia Cum Laude from the University of Helsinki, Finland, and conducted two years’ postdoctoral research in the Chemical Engineering Department at University of Wisconsin, Madison. She has published more than two dozen papers in reputed journals, and has given more than 150 presentations and 60 invited talks. She has trained ca. 60 students, including PhD, MD, MD/PhD, PharmD, and PharmD/PhD. She is a peer reviewer for more than 30 refereed journals, and serves on the editorial boards of 6 international journals. She has chaired more than 40 sessions at international conferences.

Abstract:

While new therapeutics are being developed for treating ocular diseases, the use of these therapeutics is still hampered by the need for more effective method of delivery. The reason is that these therapeutics have short half-lives, do not or hardly cross the cornea, the blood retinal barrier (BRB) and other ocular barriers, and can cause toxicity and side effects at high dose. In our Biomaterials for Translational Research Laboratory, we are interested in engineering multi-functional polymeric systems for targeted and sustained delivery of desired amount of drugs across ocular barriers to treat anterior and posterior eye diseases. In this talk, I will discuss our collaborative researches in developing i) hydrogels as subconjunctivally implantable delivery systems for sustained release of insulin to treat diabetic retinopathy; and ii) polysaccharide based nanoparticles for enhanced drug permeability across the cornea and the BRB to treat diabetic retinopathy, retinoblastoma, and glaucoma, etc.

Ruiwen Shi

Allergan Inc., USA

Title: Non‐degradable and biodegradable implants

Time : 13:40-14:00

Speaker
Biography:

Ruiwen Shi holds a Ph.D. in Pharmaceutics from the University of British Columbia and is currently a principal scientist in Allergan. He has been working in the field of local drug delivery for more than 15 years. His work in Allergan is centered around developing novel long-acting intraocular drug delivery systems for treating both front and back of the eye diseases. Prior to Allergan, he worked for Alza Corporation, Bausch + Lomb, and Mannkind Corporation and made contributions to the development of the intravitreal implant Retisert® and the rapid-acting inhaled insulin Afrezza®. Ruiwen has been very passionate about drug delivery systems and was the chair of the Ocular Drug Delivery Focus Group of the Controlled Release Society.

Abstract:

Oligonucleotides, peptides and proteins remain a significant challenge for sustained or controlled delivery. Many of these agents have been clinically validated in ophthalmology with great success as exemplified by Macugen®, Eylea® and Lucentis®. However, there remains a critical unmet medical need to sustain or target the delivery of these agents. The clinical application of macromolecule drug substances is limited due to poor bioavailability and disposition. Direct intravitreal administration of these agents mitigates the issues of poor bioavailability, however short half‐lives relative to duration of therapy results in a requirement for frequent high dose administrations. Current strategies and recent advances for the sustained delivery of macromolecules will be reviewed. Intravitreal delivery considerations for these agents not only includes sustained release, but also enhancing cellular their therapeutic profile. Prevention of aggregation and degradation in addition to sustained release are keys to enabling local delivery of these agents. In this presentation advances in the delivery of these therapeutic agents will be reviewed.

Speaker
Biography:

Richard Kenley, Ph.D. (Advantar founder and CEO), has over 30 years experience in the pharmaceutical, biotechnology, and bio-pharma contract service industries. He is an inventor on 4 patents, author of over 60 peer-reviewed scientific publications. Dr. Kenley has made major contributions to the development and eventual approval of important pharmaceuticals including: butaconozole, nafarelin (Synarel®), bone morphogenetic protein 2 (InFuse®), rhIL-11 (Neumega®), pramlintide (Symlin®), and exenatide (Byetta®). His industry assignments include senior management positions at SRI International, Syntex, Baxter, Genetics Institute (Pfizer), Amylin (Astra-Zeneca), and Cabrillo Laboratories (Catalent).

Abstract:

Objectives: To determine equilibrium binding constant (EB) values for bimatoprost and tafluprost drug product formulations in contact with Lotrafilcon A soft contact lenses and to characterize the importance of drug molecule hydrophobicity in controlling binding interactions Methods: Bimatoprost Ophthalmic Solution and Tafluprost Ophthalmic Solution (Saflutan®) drug product solutions were incubated with Lotrafilcon A lens material for timed intervals at 25 and 37 °C. Aliquots were withdrawn, filtered and tested by RP-UPLC with respect to [bimatoprost] or [tafluprost] remaining in solution. A series of homologous dialkyl phthalate esters and a series of homologous p-hydroxybenzoic acid alkyl esters were also tested as reference compounds. Results: Bimatoprost and tafluprost were both rapidly (within 15 min) absorbed from solution by Lotrafilcon A lenses, reaching equilibrium within 60 min. At any lens:solution (w/v) ratio, the extent of drug binding to lens material was greater for tafluprost than for bimatoprost. The log(EB) values correlated with solute octanol:water partition coefficient (logP) values, indicating that hydrophobic interactions are important in controlling solute partitioning into the lens material. Conclusions: This study established quantitative relationships for tafluprost and bimatoprost binding to Lotrafilcon A lenses. The fraction of either bimatoprost or tafluprost that binds to Lotrafilcon A increases with increasing lens:solution (w/v) ratio. For a 60-µL dose volume applied to a single contact lens, 16% of initially-present bimatoprost remains in solution, whereas only 6% of initially-present tafluprost remains in solution. These calculations clearly demonstrate that both drugs partition very extensively into Lotrafilcon A contact lens material. Although the clinical implications of such binding can only be surmised, it would seem prudent to caution contact lens wearers to remove the lenses before administering either prostaglandin drug.

Linda F. McElhiney

Indiana University Health, USA

Title: Preparing and obtaining quality compounded ophthalmic preparations

Time : 14:20-14:40

Speaker
Biography:

Linda McElhiney received her BS in Pharmacy from Purdue University in 1984 and her PharmD from the University of Florida in 2002. She is currently a graduate student at the University of Florida and anticipates receiving her Masters with a focus on Institutional Leadership in August 2004. She is the Compounding Pharmacy Operations Coordinator the Indiana University Health health-system, consisting of 21 hospitals. She has published more than 45 papers in peer-reviewed journals, written chapters for textbooks, and is the book author of Compounding Guide for Ophthalmic Preparations (APhA 2013). She currently serves on the USP Committee of Experts for Compounding and is a full fellow in the International Academy of Compounding Pharmacists, American Society of Health-system Pharmacists, and the American College of Apothecaries.

Abstract:

Ophthalmic medications are often compounded by medical staff, nursing staff, or pharmacists because they are not commercially available. If these medications are not properly compounded, it can result in painful infections, loss of vision, or even loss of the eye. There are USP standards on how to prepare these compounded medications in a protected environment to ensure patient safety. In 2013, Congress passed the Drug Quality and Tracking Act to set legal standards for preparing and obtaining good quality compounded medications to prevent tragedies, such as the meningitis outbreak with NECC, endotoxin contamination causing toxic anterior segment syndrome, or fungal infections from compounded brilliant blue G intravitreal injections. This presentation provides an overview on how to properly and safely prepare quality ophthalmic preparations that meet standards within a practice setting. It also provides information on how to outsource compounding services to a qualified compounding pharmacy or outsourcing facility with a review of the new Drug Quality and Tracking Act

Viral Kansara

Novartis Institutes for Biomedical Research, USA

Title: Ocular melanin modulates pharmacokinetics and drug disposition of therapeutic agents

Time : 14:40-15:00

Speaker
Biography:

Viral Kansara is the Investigator at the Novartis Institutes for Biomedical Research. He leads Ocular Pharmacokinetics and Drug Delivery laboratory within Pharmacology group. His team focuses on discovery and development of novel targets and delivery systems to treat AMD, diabetic retinopathy and glaucoma. Viral earned his Ph.D. in the field of Pharmaceutical Sciences from Ashim Mitra’s Laboratory at the University of Missouri-Kansas City. He has authored 2 book chapters and numerous research articles in reputed journals and has been serving as a reviewer for PharmRes, IOVS, AAPS PharmSciTech, and JOPT.

Abstract:

Melanin is a heterogeneous biopolymer which is present in the front and back of the eye. Due to its acidic and hydrophobic nature, many therapeutic agents bind to melanin-rich ocular tissues such as the iris-ciliary body, choroid and retinal pigment epithelium of the eye. We hypothesized that drugs with high affinity to melanin are linked to higher ocular exposure, with melanin postulated to be a potential depot for such compounds. To test this hypothesis, in vivo ocular and plasma pharmacokinetic (PK) studies of three compounds with high, medium and low melanin affinity were performed in pigmented and non-pigmented rats. Male Sprague-Dawley (non-pigmented) and Brown-Norway (pigmented) rats were used to determine ocular and plasma PK of selected compounds. The PK parameters were determined using Watson LIMS (Non-compartmental analysis). Using a high-throughput chromatography based in vitro assay, we screened 306 compounds of diverse chemical structures for their in vitro melanin affinity (67 – low-; 168 – medium-; 71 – high- affinity). In our in vivo studies, a significant increase in ocular exposures of high affinity (AUCPEC: 73µM*h vs. 2µM*h; AUCretina: 8 µM*h vs. 3µM*h) and medium affinity (AUCPEC: 9µM*h vs. 0.6µM*h; AUCretina: 6µM*h vs. 2.6µM*h) compounds were observed in pigmented rats compared with non-pigmented rats. The increased ocular exposure (in vivo) correlated with increased retention time on the chromatography (in vitro) method. This vitro assay was shown to be predictive of in vivo melanin dependent ocular compound deposition. This approach provided excellent in-vitro-in-vivo correlations (IVIVC). In conclusion, this research suggests that ocular melanin affinity modulates ocular PK and drug retention in the eye, and may influence the pharmacological action of ocular targeted therapeutic agents.

Speaker
Biography:

M.D. in 1997 and Ph.D. in 2002 from Osaka City University in Japan. Clinical training was completed in eye clinic of Osaka City University Hospital and since 2002 a specialist of ophthalmology. In 2005 started research work in University of Kiel in Germany and in 2009 moved to Institute of Biomedical Optics, University of Luebeck. Today engages in the research and clinical works in Institute of Biomedical Optics and Department of Ophthalmology, University of Luebeck. Leading some research projects related to retinal cell biology. Since 2010 adjunct lecturer of Osaka City University.

Abstract:

Autofluorescence (AF) measurement with two-photon microscopy (TPM) and fluorescence lifetime imaging (FLIM) enables the discrimination of different fluorescence molecules located in a different depth of the tissue. We investigated the AF and fluorescence lifetime (FLT) of retinal cells focusing on retinal pigment epithelial (RPE) cells and photoreceptor outer segments (POS). Lipid peroxidation was induced in the RPE and POS of the porcine explants by FeSO4, and the tissues were investigated with TPM and FLIM. Furthermore, the RPE explants were examined with immunofluorescence study for 4-hydroxynonenal (4-HNE)-adducts, adipocyte differentiation related protein (ADFP), and rhodopsin. TPM-AF in RPE cells is mostly originated from the melanosomes under normal conditions, which have a very short fluorescence lifetime (FLT) (mean=117 ps). FeSO4 exposure leads to the appearance of bright granular AF inside and around RPE cells, whose FLT is significantly longer (mean=1388 ps) than melanosome-AF. FeSO4 exposure increases the fluorescence intensity of POS-AF and shortens their FLT. In the immunofluorescence studies, strong 4-HNE staining was observed intra- and pericellularly of RPE cells under lipid peroxidation, whose localization was partially consistent with rhodopsin and ADFP, respectively, which suggests that the FeSO4-induced bright AF granules inside/around RPE cells are suggested to be the oxidized POS-membranes and the retinoid-storing inclusions, respectively. From these results, 4-HNE-adducts may be one of the main fluorophores of these AF. Since the amount of 4-HNE-adducts is suggested to reflect cellular oxidative stress status, TPM with FLIM might be a useful tool to detect oxidative stress status of RPE cells and the POS.

Break: Coffee Break 15:20-15:35 @ Prefunction Area

Kannan Rangaramanujam

Johns Hopkins School of Medicine, USA

Title: Dendrimer-based targeted nanotherapeutics for ocular inflammation

Time : 15:35-15:55

Speaker
Biography:

Kannan Rangaramanujam is a professor of ophthalmology and the center for nanomedicine at the Wilmer Eye Institute in Johns Hopkins School of Medicine. He obtained his PhD from the California Institute of Technology (1994) in Chemical Engineering, and performed post-doctoral research at the University of Minnesota. His primary research interests are in the field of dendrimer-based targeted therapeutic platforms for neuroinflammation in CNS diseases, with a focus on retinal degeneration, cerebral palsy, and traumatic brain injury. Kannan and his team have discovered ways to target neuroinflammation using dendrimers. Dr. Kannan is an author of four patents, more than 75 peer-reviewed publications. He has won several recognitions, including the NSF CAREER award, Unilever award, and is on the editorial board of Nanomedicine: nanotechnology, biology and medicine (www.cnm-hopkins.org).

Abstract:

Retinal neuroinflammation, mediated by activated microglia, plays a key role in the pathogenesis of photoreceptor and retinal pigment epithelial cell loss in age-related macular degeneration and retinitis pigmentosa. Targeted, sustained attenuation of activated microglia may be a powerful strategy to arrest retinal degeneration. Nanomedicine approaches are being explored for targeted drug therapy for attenuation of neuroinflammation in the retina was explored using hydroxyl-terminated polyamidoamine (PAMAM) dendrimer-drug conjugate nanodevices. We show that, upon intravitreal administration, PAMAM dendrimers selectively localize in activated microglia in the retina in multiple animal models of retinal degeneration, but not in the retina of healthy controls. This pathology-dependent biodistribution was exploited for drug delivery, by covalently conjugating anti-inflammatory drugs to the dendrimer. For example, a dendrimer-fluocinolone acetonide conjugate was prepared, and was released the drug in a sustained manner over 90 days. One intravitreal injection of 1µg of FA conjugated to 7µg of the dendrimer was able to arrest retinal degeneration, preserve photoreceptor outer nuclear cell counts, and attenuate activated microglia, for an entire month. These studies suggest that PAMAM dendrimers (with no targeting ligands) have an intrinsic ability to selectively localize in activated microglia, and can deliver drugs inside these cells for a sustained period for the treatment of retinal neuroinflammation. The talk will highlight the role of nanomedicine, especially dendrimers, in addressing ocular inflammation.

Timothy J McCulley

Johns Hopkins School of Medicine, USA

Title: Update on management of orbital inflammation

Time : 15:55-16:15

Speaker
Biography:

McCulley currently serves as Vice Chair of Clinical Strategic Planning at the Wilmer Eye Institute, Johns Hopkins School of Medicine. In 1995 he obtained his medical degree at Washington University School of Medicine in St Louis. After a combined medical and surgical internship at the University of Hawaii, he completed residency in Ophthalmology at Stanford University in 1999. Following one year fellowship training in neuro-ophthalmology at The Bascom Palmer Eye Institute, he completed two years of fellowship training in ophthalmic plastic and reconstructive surgery at the Cincinnati Eye Institute in 2003.

Abstract:

When approaching a patient with an inflamed orbit, The most troubling aspect is often diagnosis. When no cause is identified, as a diagnosis of exclusion, we label patients with the term idiopathic orbital inflammatory syndrome (IOIS). On initial evaluation, a primary goal is to identify infectious and/or systemic disease. Often a thorough history can help guide further evaluation. Imaging is usually obtained urgently and can particularly useful in identifying infection. When initial evaluation is indicative of IOIS, rapid resolution follows immunosuppression, which is tailored to severity. In atypical, steroid resistant or recurrent cases serologic evaluation and biopsy may be indicated. In this talk, recent advances in imaging and management of patients presenting with an inflamed orbit will be discussed. Focus will also be placed on identifying patients with potentially sight threatening or fatal diseases which may present similarly to IOIS.

  • Track 7: Novel Approaches to Ophthalmology Therapeutics
Location: Harbor Room
Speaker

Chair

Ashim K. Mitra

University of Missouri-Kansas City School of Pharmacy, USA

Speaker

Co-Chair

Kay Rittenhouse

Ocular Drug Development Strategies LLC, USA

Session Introduction

Ashim K. Mitra

University of Missouri-Kansas City School of Pharmacy, USA

Title: Emerging technologies in controlled long term delivery of ocular therapeutics

Time : 09:00-09:20

Speaker
Biography:

Mitra received his Ph.D. in Pharmaceutical Chemistry in 1983 from the University of Kansas. He is currently a Curator’s Professor of Pharmacy at the University of Missouri-Kansas City. He is also the Vice Provost for Interdisciplinary Research and Chairman of the Division of Pharmaceutical Sciences, and Co-director of the Vision Research Center at the University of Missouri-Kansas City School of Medicine. He has conducted extensive research in various drug delivery technologies, including ocular drug delivery for the past three decades. He has published nearly 300 peer reviewed scientific research and review articles in high impact international journals. He has presented over 350 abstracts at scientific meetings, including the annual American Association of Pharmaceutical Scientists (AAPS), the Society of Toxicology, and The Association for Research in Vision and Ophthalmology (ARVO) conferences, and has given over 100 presentations to a wide audience (including several universities, pharmaceutical companies and scientific organizations).

Abstract:

Current macromolecular delivery in the treatment of diabetic retinopathy and wet-AMD (age-related macular degeneration) requires frequent intravitreal injections to maintain therapeutic levels at retina/choroid. Frequent intravitreal administrations can cause potential complications like endophthalmitis, retinal detachment, retinal hemorrhage, and patient noncompliance. Studies with marketed polymers (poly (lactic-co-glycolic acid) (PLGA)) suggest that acidic pH in the core of nanoparticles significantly reduces biological activity of therapeutic proteins. In our laboratory, we have recently developed and evaluated novel tailor-made pentablock (PB) copolymers for semi-invasive controlled delivery of therapeutic proteins to back of the eye tissues (retina-choroid). PB copolymers were synthesized utilizing various FDA approved biodegradable and biocompatible polymer blocks (polyglycolide (PGA), polyethylene glycol (PEG), polylactide (PLA) and polycaprolactone (PCL). These PB copolymers have been optimized with respect to molecular weight and ratios of each block in order to develop a successful macromolecular (model proteins such as lysozyme, BSA, IgG, and IgG-Fab) drug delivery system. High molecular weight PB copolymers with the block arrangement of PGA-PCL-PEG-PCL-PGA and PLA-PCL-PEG-PCL-PLA were utilized to prepare protein encapsulated nanoparticulate formulation. Whereas, PB copolymers with low molecular weight and different arrangement of blocks i.e., PEG-PCL-PLA-PCL-PEG were developed to formulate thermosensitive gel. In-vitro release studies performed with IgG-Fab and IgG-encapsulated nanoparticles exhibited a phase of burst release followed by controlled release up to ~32 and ~45 days, respectively. Interestingly, burst release phase was eliminated by dispersing nanoparticles in thermosensitive gel. By suspending IgG-Fab and IgG-loaded nanoparticles in thermosensitive gel, a continuous zero-order drug release was achieved up to ~45 and ~60 days, respectively. Moreover, biocompatible nature of novel PB copolymers was confirmed by in-vitro cytotoxicity and biocompatibility studies. This novel approach can act as a platform for ocular delivery of therapeutic biologics, which can minimize/eliminate side effects associated with frequent intravitreal injections. These results suggest tremendous applicability of PB copolymers in the development of drug delivery system which may not be limited to ocular formulations.

Kay D. Rittenhouse

Ocular Drug Development Strategies LLC, USA

Title: siRNAs – Are they A viable therapeutic approach for eye diseases?

Time : 09:20-09:40

Speaker
Biography:

Kay Rittenhouse has an extensive career in ophthalmic drug research and development, spanning from drug discovery, translational research, clinical development through launch. She has developed drug targets presented on platforms such as small molecules, aptamers, antibodies, and siRNAs. She is a sought after presenter and chair of scientific conferences and forums and has published abstracts, book chapters, and manuscripts for peer reviewed journals. Her drug development expertise includes indications such as glaucoma, retinal diseases such as diabetic retinopathy and AMD, uveitis, and diseases of the ocular surface. She received a Ph.D. in pharmacokinetics from the University of North Carolina at Chapel Hill. Her dissertation research explored the pharmacodynamics of glaucoma drugs and special expertise in ocular microdialysis. She has pharmaceutical industry experience, having worked at Alcon Laboratories, Bausch and Lomb, and Pfizer.

Abstract:

The platforms currently employed in the treatment of retinal diseases include small molecules such as fluocinolone acetonide (Retisert®) and dexamethasone (Ozurdex®), and large molecular entities such as aptamers (Macugen®), Fabs (Lucentis®), and Mabs (off label Avastin®). Other therapeutic approaches such as siRNAs, gene therapy, and nanomedicine, have been examined in ophthalmic clinical trials. In the context of delivery of therapeutics with sustained exposure to intraocular tissues, molecules like siRNAs or approaches such as gene delivery would appear to be optimal platforms, especially for targeting retinal neurons, which are non-mitotic cells. However, significant challenges have been encountered, and the horizon for therapeutic success seems cloudy due to the many clinical trial failures. This talk will discuss recent victories and challenges in gene silencing (siRNA’s) and gene delivery (AAV) and highlight potential strategies for future success.

Hu Yang

Virginia Commonwealth University, USA

Title: A new platform for sustained topical delivery of antiglaucoma drugs

Time : 09:40-10:00

Speaker
Biography:

Hu Yang is an Associate Professor in the Department of Biomedical Engineering at Virginia Commonwealth University. He has completed his Ph.D. from University of Akron in 2004 and conducted postdoctoral studies from University of Wisconsin-Madison School of Pharmacy. His research interests include dendrimer-based drug and gene delivery, nanomedicine, and novel polymers for pharmaceutical applications. He has won NSF CAREER Award and Wallace H. Coulter Translational Research Award.

Abstract:

Glaucoma is a leading cause of blindness in the world. Glaucoma therapy typically begins with topical medications. Unfortunately, antiglaucoma drugs in form of eye drops are topically administered 1-3 times daily. This need for frequent dosing with multiple medications makes compliance difficult. Longer-acting formulations and combinations which require less frequent administration might improve compliance and therefore medication effectiveness. Recently, we developed a novel ocular drug delivery system, namely dendrimer hydrogel platform (DH), for delivering antiglaucoma drugs topically. This platform is designed to deliver glaucoma drugs to the eye efficiently and release the drug in a slow fashion. Furthermore, this delivery platform is designed to be compatible with many of the glaucoma drugs that are currently approved for use. In this presentation, we will discuss this new delivery system with an emphasis on its structural features, properties, and pre-clinical results in glaucoma treatment. In addition, new chemistries developed to address effectiveness and safety of the dendrimer-based formulations will be discussed.

Speaker
Biography:

Ruslan Grishanin has completed his Ph.D. in biochemistry from Moscow State University, Russia. His postdoctoral research was focused on molecular mechanisms of exocytosis in neurons and endocrine cells and role of BDNF through TrkB signaling in the development of retinal architecture and function. In 2008 he joined Pfizer, where he led efforts in the development of treatment for age related macular degeneration, neuroprotection strategy for glaucoma, as well as in the design of novel cancer immunotherapy.

Abstract:

Geriatric retinal-degenerative diseases such as age-related macular degeneration (AMD) and glaucoma share certain pathological features with Alzheimer's disease (AD) including accumulation of extracellular deposits containing amyloid β (Aβ) peptides. Immunotherapy targeting the Aβ is being investigated as a potential treatment for the treatment of AMD and glaucoma. In this study we assessed the feasibility of the viral delivery of humanized therapeutic Aβ antibody to the retinal pigmented epithelium and retinal cells, for the continuous production of the anti-Aβ antibody in the eye in preclinical animal models.
Methods: RN6G is a humanized monoclonal antibody that recognizes both Aβ40 and Aβ42 species associated with pathology, but not the non-pathogenic amyloid precursor protein (APP). For viral delivery, RN6G was engineered as monocistronic cassette with a 2A self-cleavage linker sequence between the heavy and light antibody chains. This antibody expression cassette was delivered to retina in mice using a recombinant AAV vector. The vector was injected either subretinally, or intravitreally into C57B6 mice.
Results: Analysis of tissue distribution and pharmacokinetics indicated that antibody expression was limited to a subpopulation of cells in the ganglion cell layer following intravitreal delivery. In contrast, after subretinal delivery, full length and pharmacologically active RN6G was stably expressed in the retinal pigment epithelium (RPE). Intraocular levels of antibody were significantly higher than serum levels. Intraretinal expression of RN6G did not impair retinal function measured by electroretinogram.
Conclusion: Full length therapeutic anti-Aβ IgG engineered as a monocistronic cassette with 2A self-cleavage site can be successfully delivered to retina via rAAV vector. Since complete IgGs are stable molecules with low immunogenicity, this technology allows the investigation of targeting Aβ in retinal degenerative diseases in animal models. Furthermore, the technology may provide a way for the continuous delivery of therapeutic antibodies to treat chronic retinal degenerative diseases, if proven safe and effective in humans.

Speaker
Biography:

Byrne is the Daniel F. & Josephine Breeden Distinguished Associate Professor at Auburn University and co-founder/CTO of OcuMedic, Inc., a drug delivery company in Auburn, AL. Dr. Byrne is a leader in the field of biomaterials engineering, controlled therapeutic delivery, polymer engineering, and biomedical devices. He has made significant and sustained contributions to the field of ocular drug delivery and is a pioneer in the evolving field of contact lens delivery. His group was the first to demonstrate controlled and extended release of therapeutics from novel contact lenses based on a rational design strategy of macromolecular memory of flexible polymer chains, via a fundamental analysis of biological mechanisms of action. In 2011, he published groundbreaking results and the first in vivo evidence that a steady, effective concentration of drug can be maintained in the tear film from a contact lens for the entire duration of lens wear (J Control Release, 157(3):391‐397, 2012). The current standard of care, eye drops, had ~100 times less bioavailability. During his nine years on the Auburn faculty, he has won numerous awards for his teaching and research, licensed a number of technologies, and his research work has appeared in the popular press and television on a number of occasions. Dr. Byrne has published over 75 peer-reviewed publications and has given over 200 scientific conference presentations and invited lectures at companies, universities, and international meetings, and he is an inventor on 8 issued patents (with another 4 pending). In 2011, for his contributions to the field, Dr. Byrne was inducted as a Fellow in the American Institute for Medical & Biological Engineering (AIMBE). He has held a number of leadership roles in professional organizations and currently serves on four editorial boards. He has also developed and organized over 45 scientific and technical sessions at national and international conferences, including the US National Academy of Engineering. At Auburn, his work has been funded by numerous government agencies including NIH and NSF, and he teaches both graduate and undergraduate courses as well as directs a US Department of Education Program in Biological & Pharmaceutical Engineering and an NSF REU Site in Micro/Nano-Structured Materials, Therapeutics, & Devices. Dr. Byrne holds a BS in Chemical Engineering/Biomedical Engineering from Carnegie Mellon & MS/Ph.D. degrees in Chemical Engineering from Purdue University.

Abstract:

It is an exciting time within the field of ophthalmic drug administration, with new methods of delivery showing tremendous promise. The ‘go to’ products are topical eye drops, which are grossly inefficient delivery vehicles that hold 90% of the ocular pharmaceutics market. With a market valued at ~$15 billion and growing at an 8-10% compound annual growth rate, there is a substantial opportunity for the commercialization of new products that deliver therapeutics more effectively and efficiently to the eye. The creation of enhanced ocular delivery systems has tremendous promise to profoundly impact ocular health via improved treatment options, which will greatly improve quality of life. This presentation will involve a discussion of the challenges and opportunities associated with ocular delivery and one of the most recent novel drug delivery materials, therapeutic contact lenses. Within my research group, we have created a platform technology and a number of novel contact lenses with controlled transport of various therapeutics that can deliver constant amounts of medication to the eye for the duration of lens wear from days to weeks. In comparison, topical eye drops were ~100 times less effective when tested in vivo. Strict control of release is accomplished by engineering the architectural design of biomaterials at the molecular level. Characterization analysis of the network structure of the network in terms of molecular weight between crosslinking points, mesh size, and diffusion studies provides an aid to optimizing the design and begins to answer fundamental questions on the nature of the release control and extended delivery on the chain level. Our research also includes more comfortable and healthy contact lenses, by the controlled release of wettability/comfort agents, which is also one of the most important challenges within the lens industry.

Break: Coffee Break 10:40-10:55 @ Prefunction Area

Ashwath Jayagopal

Vanderbilt Eye Institute, USA

Title: Nanotechnology guided delivery of siRNA in retinal vascular disease

Time : 10:55-11:15

Speaker
Biography:

Ash Jayagopal is an Assistant Professor of Ophthalmology and Visual Sciences at the Vanderbilt Eye Institute of Vanderbilt University Medical Center in Nashville, TN. He also holds an appointment in Molecular Physiology and Biophysics at Vanderbilt. A biomedical engineer by training, Dr. Jayagopal’s research interests are focused on imaging and therapy of diabetic retinopathy and neovascular age related macular degeneration. He is a recipient of the 2013 Dolly Green Special Scholar Award from Research to Prevent Blindness. His research program is currently funded by the National Eye Institute, American Diabetes Association, American Health Assistance Foundation, Research to Prevent Blindness, and the International Retinal Research Foundation.

Abstract:

Cell adhesion molecules (CAMs) are markers of inflammation expressed on retinal endothelial cell surfaces in a broad spectrum of ocular vascular diseases, including retinal neovascularization, and therefore constitute potential targets for promoting homing, binding, and internalization of nanoscale imaging and therapeutic agents. We have developed a series of nanocarriers targeted against CAMs which can bear imaging or therapeutic payloads and deliver them to the cytoplasm of dysfunctional endothelial cells. The goal of this study was to demonstrate the utility of CAM targeted nanocarriers for site‐specific delivery of antiangiogenic siRNAs in two animal models of retinal neovascularization. CAM targeted nanocarriers bearing VEGFR2 siRNAs were synthesized and characterized to determine optimal size, surface charge, and encapsulation efficiencies. Cytotoxicity, delivery efficiency, and functional knockdown of several molecular targets were determined in retinal microvascular endothelial cells. Biodistribution and efficacy of nanocarriers in animal models of laser‐induced choroidal neovascularization and oxygen‐induced retinopathy were analyzed. CAM targeted nanocarriers were capable of specific targeting of ICAM‐1, endoglin, and VCAM‐1 on inflamed retinal endothelial cells in vitro, and triggered release of siRNA following internalization was observed. Specific targeting of neovascular endothelial cells was observed in both animal models of vascular disease, using CAMs on neovessel endothelial cells as a portal for delivery of therapy. Knockdown of molecular targets via siRNAs was achieved in vitro and in vivo without adverse effects on cell and tissue function. CAM targeted nanocarriers are a promising framework for the delivery of diverse imaging and therapeutic payloads to diseased retinal endothelial cells in vivo.

Speaker
Biography:

Beniamino Palmieri is a professor of Experimental Clinical Surgery, University of Modena, Italy. He runs an experimental and clinical group with original studies addressed to: new lactobacilli utilization in supporting tissues and organs failure, and new natural compounds use especially in antioxidant and preventive clinical setting. New diagnostics and therapeutic devices mainly based on point of care philosophy with high standardization criteria.

Abstract:

Keratoconjunctivitis sicca (KCS) is a corneo-conjunctiva progressive inflammatory disease affecting either humans and dogs with tears production impairment and several ocular symptoms triggered by autoimmune imbalance. Cyclosporine and tacrolimus ointment, steroids drops and artificial tearsis the gold standard treatment. Our study is addressed to evaluate the complementary role of 2 months, administerednutraceutical food, in dogs whose immuno-suppressive treatment had proven inadequate. The formula encloses fish proteins, rice carbohydrates, mellonsuperoxid dismutase, Ascophyllum, Astaxantina, Aloe vera, papaya, Punica granatum, Green tea, Polygonum L., Curcuma, Piper nigrum, Zinc and an Omega3/6 ratio of 1:0.8. The trial involved two group of animals: in the first group, unsatisfactorily responsive to the integrative feeding, after 30 days, the complementary effect of the functional food, joined with the local treatment, gave 120% Schirmer Test improvement and reduction of mean conjunctivitis intensity: 70%, cheratitis lesions: 65%, corneal pigmentation:50% and mucus production 80%.
In the second group exclusively cured with the long term diet administration, a drop out of intraocular treatment was attempted to evaluate if functional feeding would support prolonged or permanent control of the symptoms.
In 45% animals it was possible to definitely withdraw immunosuppressive treatment, with artificial tears administration follow up. The ongoing study is investigating whether the exclusion of the nutraceutical food might be responsible of KCS relapse or not. Translating our experimental pet investigation, in the human setting, the nutraceutical food administration in Sjogren syndrome should be challenged to relieve the symptoms and improve the life quality of the affected patients.

Speaker
Biography:

Sai HS Boddu is an Assistant Professor at The University of Toledo, College of Pharmacy and Pharmaceutical Sciences.He received his Ph.D. in Pharmaceutical Sciences from The University of Missouri-Kansas City (UMKC) in Dec, 2010.He has also received a Bachelor of Pharmaceutical Sciences degree (B. Pharmacy) along with the professional pharmacist licensure and Master’s in Pharmaceutics from India. Dr. Boddu’s research areas include Drug Delivery, Bioanalysis, and Pharmacokinetics. He authored and co-authored more than 25 research and review articles in various peer reviewed journals. He also made significant contribution in 6 book chapters.

Abstract:

The present study deals with the development and characterization of a mixed nanomicellar eye drop formulation of dexamethasone (DEXSOLV) and effectively deliver the drug to the retina following topical administration forthe treatment of posterior uveitis.Mixed nanomicelleswere formulated using nonionic surfactant moleculespolysorbate 80 (P80) and polyoxyl 40 stearate (P40S). Nanomicelles were characterized for size, zeta potential, morphology, clarity,surface tension, and dilution stability in artificial tears. Ocular tolerance and tissue distribution of dexamethasone were studied following single and repeated topical administrations of DEXSOLV in rabbits. The nanomicellar formulation of dexamethasone (0.1%) with an optimized composition of P40S/P80=7/3 by weight was clear with a particle size of about 14.5nm. The absorbance of DEXSOLV was found to be less than 0.1 at 400nm. Transmission electron microscopy images revealed the spherical structure of micelles. DEXSOLV was found to be stable at 4 degC and 25 degC for up to 6 months. No irritation or redness was observed in the treated eyes as compared to the untreated control rabbit eyes. Therapeutic concentrations of dexamethasone were observed in various anterior and posterior segment tissues, including retina-choroid, suggesting the effectiveness of topical therapy in posterior uveitis. In conclusion, the nanomicelles of P40S and P80 could efficiently solubilize dexamethasone, a lipophilic drug, in their cores resulting in a stable aqueous eye drop formulation. Using this eye drop formulation, dexamethasone concentrations could be maintained well above the minimum effective concentrations following topical administration.

Speaker
Biography:

Anne Beable graduated from Bristol University (MB ChB) in 1977. She worked as an NHS General Medical Practitioner until ill-health retirement in 2007. Subsequently she developed her interest in Western Medical Acupuncture (WMA) and gained an MSc with Distinction from the University of Hertfordshire in 2012. She is an accredited member of the British Medical Acupuncture Society (BMAS). The publication of this case report in the Pubmed-indexed journal Acupuncture in Medicine was her first attempt at submitting an article for publication.

Abstract:

A patient with apparently well-controlled epilepsy had a painful musculoskeletal condition was treated successfully with two sessions of acupuncture. However, 4 hours after the first treatment and during the second, an adverse event involving impairment of consciousness occurred. The patient subsequently experienced an increased frequency of complex partial seizures resulting in the loss of his driving license. A detailed retrospective review of the past medical history indicated that the patient probably had comorbidities in the form of rapid eye movement behavior disorder and dysfunctional somatosensory/vestibular processing. Acupuncture may have triggered the adverse event via shared neurosubstrates. This adverse event raises the possible implications regarding safe acupuncture practice.

Shlomit Schaal

University of Louisville, USA

Title: Engineering an end to post-vitrectomy cataracts

Time : 12:15-12:35

Speaker
Biography:

Shlomit Schaal is a clinician-scientist and a vitreo-retinal surgeon specializing in the surgical and medical management of complex vitreo-retinal diseases, such as age-related macular degeneration, diabetic retinopathy, retinal detachment and retinal vascular diseases. She completed her ophthalmology residency at Rambam Medical Center in Israel, her Ph.D. program at the Technion Institute of Technology, and her vitreo-retina fellowship at the University of Louisville. She is currently an Associate Professor at the University of Louisville, where she is the Director of Retina, the Director of Fellowship Program in Vitreo-Retinal Diseases and Surgery, and the Director of Diabetic Retinopathy Service. Dr. Schaal is an active member of the American Society of Retina Specialists, the Macula Society, the Retina Society, the American Academy of Ophthalmology, and the Association for Research in Vision and Ophthalmology.

Abstract:

To report the result of the ability of a biocompatible photopolymerizable gel to prevent cataract formation after vitrectomy. Purpose: To develop a biocompatible photopolymerizable gel to seal off the crystalline lens against oxygen diffusion to avoid cataract formation after vitrectomy and to test its capability in vitro and in vivo. Methods: A composite gel was formulated to meet preset criteria: viscoelasticity; spreadability; smoothness; ability to polymerize in situ; optical clarity; cohesiveness to remain adherent to lens capsule; iso-osmolarity; biocompatibility; oxygen impermeability; refractive index close to lens; surface energy >40 dyne/cm to avoid protein and cell adhesion; elastic modulus >40 N/m2 to preserve lens accommodation, and biodurability. The gel was tested on ex vivo porcine lenses for its ability to prevent cataract formation. The gel was also tested in vivo by injecting pigs’ eyes after 25-gauge vitrectomy. Lens clarity was compared with vitrecomized but uncoated control eyes for up to 3 months. Results: Ninety different permutations of the ingredients were tested for their conformity to the required criteria. The optimum results were obtained by mixing 100 mg/mL PEG (6000 Da) with 10 mg/mL of HA (viscosity 5200 mP.sec) and photoinitiating under green LED source with Eosin Y/triethanolamine/N-vinylpyrrolidone added to PEG-polymer solutions to complex with the acrylate groups on the PEG molecules in a 1.2/1 ratio. The resultant clear (265-800 nm) gel had perfect spreadability, leveling, coverage, durability and cohesiveness with a thermally stable (25-37 °C) refractive index of 1.33, surface energy of 66 dyne/cm, and elastic modulus of 41.4 N/m2. The gel resists protein and cell adhesion, and reduces oxygen diffusion 34 times. The biogel also proved to be biocompatible with porcine lenses in the ex vivo studies and significantly delayed the development of lenticular opacities without any apparent side effects. Conclusion: Formulated biogels can limit oxygen diffusion to crystalline lens. This technology can eliminate tedious head-down positioning and cataract formation after vitrectomy surgery.

Break: Lunch Break 12:35-13:20 @ Annapolis Room