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Browsing by Author "Ciulla, Thomas A."
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Item The acute and chronic effects of intravitreal anti-vascular endothelial growth factor injections on intraocular pressure: A review(Elsevier, 2017) Bracha, Peter; Moore, Nicholas A.; Ciulla, Thomas A.; WuDunn, Darrell; Cantor, Louis B.; Department of Ophthalmology, School of MedicineThe acute and chronic effects of repeated intravitreal antivascular endothelial growth factor (VEGF) injections on intraocular pressure have not been fully characterized, and the development of sustained ocular hypertension could adversely affect patients who are at risk of glaucomatous optic neuropathy. As expected, volume-driven, acute ocular hypertension immediately follows intravitreal injection, but this pressure elevation is generally transient and well tolerated. Several medications have been investigated to limit acute ocular hypertension following anti-VEGF therapy, but the benefits of pretreatment are not conclusive. Chronic, sustained ocular hypertension, distinct from the short-term acute ocular hypertension after each injection, has also been associated with repeated intravitreal anti-VEGF injections. Risk factors for chronic ocular hypertension include the total number of injections, a greater frequency of injection, and preexisting glaucoma. Proposed mechanisms for chronic ocular hypertension include microparticle obstruction, toxic or inflammatory effects on trabecular meshwork, as well as alterations in outflow facility by anti-VEGF agents. Although limiting anti-VEGF therapy could minimize the risk of both acute and chronic ocular hypertension, foregoing anti-VEGF therapy risks progression of various macular diseases with resulting permanent central vision loss. While definitive evidence of damage to the retinal nerve fiber layer is lacking, patients receiving repeated injections should be monitored for ocular hypertension and patients in whom sustained ocular hypertension subsequently developed should be periodically monitored for glaucomatous changes with optic nerve optical coherence tomography and static visual fields.Item Challenges of cost-effectiveness analyses of novel therapeutics for Inherited Retinal Diseases(Elsevier, 2022) Jayasundera, K. Thiran; Abuzaitoun, Rebhi O.; Lacy, Gabrielle D.; Abalem, Maria Fernanda; Saltzman, Gregory M.; Ciulla, Thomas A.; Johnson, Mark W.; Ophthalmology, School of MedicinePurpose: To investigate the challenges and potential improvement strategies of cost-effectiveness analyses performed for therapeutics targeting inherited retinal diseases (IRDs). Design: Perspective. Methods: A literature review was conducted with discussion of current limitations and improvement recommendations. Results: Cost-effectiveness analysis (CEA) performed for IRD therapeutics has multiple limitations. First, the available methods used to measure health-related quality of life and health utilities can be inaccurate when used in IRDs. Second, the financial burden to patients and society from vision impairment associated with IRDs has been inadequately studied and includes a variety of expenditures ranging from direct costs of IRD specialty health care to indirect expenses associated with daily living activities. Third, our collective understanding is limited in the areas of IRD natural history and health benefits gained from new IRD treatments (eg, gene therapies). In addition, the therapeutic effect from a patient perspective and its duration of action are not fully understood. Due to the scarcity of data, CEA for newly approved therapies has relied on assumptions and creations of predictive models for both costs and health benefits for these new therapeutics in order to calculate the incremental cost-effectiveness ratio. Conclusions: CEA studies performed for IRD therapeutics have been limited by the established health utilities in ophthalmology and the lack of disease-specific information. The assumptions and extrapolations in these studies create substantial uncertainty in incremental cost-effectiveness ratio results. An improved framework is required for CEA of IRD therapeutics in order to determine the cost-effectiveness of each therapy brought from clinical trials to clinical practice.Item Diabetic Retinopathy in the Aging Population: A Perspective of Pathogenesis and Treatment(Dovepress, 2021-07-15) Leley, Sameer P.; Ciulla, Thomas A.; Bhatwadekar, Ashay D.; Ophthalmology, School of MedicineThe elderly population in the United States is projected to almost double by the year 2050. In addition, the numbers of diabetics are rising, along with its most common complication, diabetic retinopathy (DR). To effectively treat DR within the elderly population, it is essential first to consider the retinal changes that occur due to aging, such as decreased blood flow, retinal thinning, and microglial changes, and understand that these changes can render the retina more vulnerable to oxidative and ischemic damage. Given these considerations, as well as the pathogenesis of DR, specific pathways could play a heightened role in DR progression in elderly patients, such as the polyol pathway and the vascular endothelial growth factor (VEGF) axis. Current ocular treatments include intravitreal corticosteroids, intravitreal anti-VEGF agents, laser photocoagulation and surgical interventions, in addition to better control of underlying diabetes with an expanding range of systemic treatments. While using therapeutics, it is also essential to consider how pharmacokinetics and pharmacodynamics change with aging; oral drug absorption can decrease, and ocular drug metabolism might affect the dosing and delivery methods. Also, elderly patients may more likely be nonadherent to their medication regimen or appointments than younger patients, and undertreatment with anti-VEGF drugs often leads to suboptimal outcomes. With a rising number of elderly DR patients, understanding how aging affects disease progression, pharmacological metabolism, and adherence are crucial to ensuring that this population receives adequate care.Item Disease progression pathways of wet AMD: opportunities for new target discovery(Taylor & Francis, 2022) Wolf, Amber T.; Harris, Alon; Oddone, Francesco; Siesky, Brent; Verticchio Vercellin, Alice; Ciulla, Thomas A.; Ophthalmology, School of MedicineIntroduction: Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among people age 60 years or older in developed countries. Current standard-of-care anti-vascular endothelial growth factor (VEGF) therapy, which inhibits angiogenesis and vascular permeability, has been shown to stabilize choroidal neovascularization and increase visual acuity in neovascular AMD. However, therapeutic limitations of anti-VEGF therapy include limited durability with consequent need for frequent intravitreal injections, and a ceiling of efficacy. Current strategies under investigation include targeting VEGF-C and VEGF-D, integrins, tyrosine kinase receptors, and the Tie2/angiopoietin-2 pathway. A literature search was conducted through November 30, 2021 on PubMed, Medline, Google Scholar, and associated digital platforms with the following keywords: wet macular degeneration, age-related macular degeneration, therapy, VEGF-A, VEGF-C, VEGF-D, integrins, Tie2/Ang2, and tyrosine kinase inhibitors. Areas covered: The authors provide a comprehensive review of AMD disease pathways and mechanisms involved in wet AMD as well as novel targets for future therapies. Expert opinion: With novel targets and advancements in drug delivery, there is potential to address treatment burden and to improve outcomes for patients afflicted with neovascular AMD.Item Efficacy of Dexamethasone Intravitreal Implant For Refractory Macular Edema Caused by Retinal Vein Occlusion(Wolters Kluwer, 2018-10) Hussain, Rehan M.; Ciulla, Thomas A.; Ciulla, Lauren M.; Sink, Bethany; Harris, Alon; Ophthalmology, School of MedicinePurpose: To investigate efficacy of dexamethasone intravitreal (DEX) implant in treating refractory macular edema caused by retinal vein occlusion. Methods: Retrospective chart review. Results: Twenty-two eyes with refractory macular edema caused by retinal vein occlusion were treated with a mean of 2.2 DEX over 12 months. Patient had previously received a mean of 7 treatments (laser, bevacizumab, and/or triamcinolone) for macular edema present for at least 4 months duration (mean 20.8 ± 17.6 months, range 4–72 months) before starting DEX. Mean baseline visual acuity was 20/91, and mean central subfield thickness was 506 μm. DEX improved mean best-corrected visual acuity to 20/75 and 20/66 at 7 weeks and 6 months follow-up, although it worsened to 20/132 at 12 months. Mean central subfield thickness improved to 292, 352, and 356 μm at 7 weeks, 6 months, and 12 months follow-up, respectively. There was a statistically significant association between number of DEX treatments and central subfield thickness (P = 3.28 × 10−9). There was a statistically significant association between number of days followed and best-corrected visual acuity (P = 0.006). Six of 12 (50%) phakic patients developed visually significant cataract requiring surgery. Five of 22 (23%) patients developed ocular hypertension (intraocular pressure > 30) and consequently did not undergo further treatment with DEX. Conclusion: DEX resulted in sustained anatomical reduction of retinal vein occlusion–associated refractory macular edema, although this did not translate into long-term best-corrected visual acuity improvement in either phakic or pseudophakic patients, possibly related to chronic structural alterations in the retina despite reduction of edema.Item Gene Therapy for Inherited Retinal and Optic Nerve Degenerations(Taylor & Francis, 2018) Moore, Nicholas A.; Morral, Nuria; Ciulla, Thomas A.; Bracha, Peter; Ophthalmology, School of MedicineIntroduction: The eye is a target for investigational gene therapy due to the monogenic nature of many inherited retinal and optic nerve degenerations (IRD), its accessibility, tight blood-ocular barrier, the ability to non-invasively monitor for functional and anatomic outcomes, as well as its relative immune privileged state.Vectors currently used in IRD clinical trials include adeno-associated virus (AAV), small single-stranded DNA viruses, and lentivirus, RNA viruses of the retrovirus family. Both can transduce non-dividing cells, but AAV are non-integrating, while lentivirus integrate into the host cell genome, and have a larger transgene capacity. Areas covered: This review covers Leber’s congenital amaurosis, choroideremia, retinitis pigmentosa, Usher syndrome, Stargardt disease, Leber’s hereditary optic neuropathy, Achromatopsia, and X-linked retinoschisis. Expert opinion: Despite great potential, gene therapy for IRD raises many questions, including the potential for less invasive intravitreal versus subretinal delivery, efficacy, safety, and longevity of response, as well as acceptance of novel study endpoints by regulatory bodies, patients, clinicians, and payers. Also, ultimate adoption of gene therapy for IRD will require widespread genetic screening to identify and diagnose patients based on genotype instead of phenotype.Item Gene Therapy for Non-Hereditary Retinal Disease: Age-Related Macular Degeneration, Diabetic Retinopathy, and Beyond(MDPI, 2024-06-01) Rowe, Lucas W.; Ciulla, Thomas A.; Ophthalmology, School of MedicineGene therapy holds promise as a transformative approach in the treatment landscape of age-related macular degeneration (AMD), diabetic retinopathy (DR), and diabetic macular edema (DME), aiming to address the challenges of frequent intravitreal anti-vascular endothelial growth factor (VEGF) injections. This manuscript reviews ongoing gene therapy clinical trials for these disorders, including ABBV-RGX-314, ixoberogene soroparvovec (ixo-vec), and 4D-150. ABBV-RGX-314 utilizes an adeno-associated virus (AAV) vector to deliver a transgene encoding a ranibizumab-like anti-VEGF antibody fragment, demonstrating promising results in Phase 1/2a and ongoing Phase 2b/3 trials. Ixo-vec employs an AAV2.7m8 capsid for intravitreal delivery of a transgene expressing aflibercept, showing encouraging outcomes in Phase 1 and ongoing Phase 2 trials. 4D-150 utilizes an evolved vector to express both aflibercept and a VEGF-C inhibitory RNAi, exhibiting positive interim results in Phase 1/2 studies. Other therapies reviewed include EXG102-031, FT-003, KH631, OLX10212, JNJ-1887, 4D-175, and OCU410. These therapies offer potential advantages of reduced treatment frequency and enhanced safety profiles, representing a paradigm shift in management towards durable and efficacious cellular-based biofactories. These advancements in gene therapy hold promise for improving outcomes in AMD and addressing the complex challenges of DME and DR, providing new avenues for the treatment of diabetic eye diseases.Item Genetics of Diabetic Retinopathy, a Leading Cause of Irreversible Blindness in the Industrialized World(MDPI, 2021-07-31) Bhatwadekar, Ashay D.; Shughoury, Aumer; Belamkar, Ameya; Ciulla, Thomas A.; Ophthalmology, School of MedicineDiabetic retinopathy (DR) is a chronic complication of diabetes and a leading cause of blindness in the industrialized world. Traditional risk factors, such as glycemic control and duration of diabetes, are unable to explain why some individuals remain protected while others progress to a more severe form of the disease. Differences are also observed in DR heritability as well as the response to anti-vascular endothelial growth factor (VEGF) treatment. This review discusses various aspects of genetics in DR to shed light on DR pathogenesis and treatment. First, we discuss the global burden of DR followed by a discussion on disease pathogenesis as well as the role genetics plays in the prevalence and progression of DR. Subsequently, we provide a review of studies related to DR's genetic contribution, such as candidate gene studies, linkage studies, and genome-wide association studies (GWAS) as well as other clinical and meta-analysis studies that have identified putative candidate genes. With the advent of newer cutting-edge technologies, identifying the genetic components in DR has played an important role in understanding DR incidence, progression, and response to treatment, thereby developing newer therapeutic targets and therapies.Item Induced pluripotent stem cell-based therapy for age-related macular degeneration(Taylor & Francis, 2017) Bracha, Peter; Moore, Nicholas A.; Ciulla, Thomas A.; Ophthalmology, School of MedicineIntroduction: In age-related macular degeneration (AMD), stem cells could possibly replace or regenerate disrupted pathologic retinal pigment epithelium (RPE), and produce supportive growth factors and cytokines such as brain-derived neurotrophic factor. Induced pluripotent stem cells (iPSCs)-derived RPE was first subretinally transplanted in a neovascular AMD patient in 2014. Areas covered: Induced PSCs are derived from the introduction of transcription factors to adult cells under specific cell culture conditions, followed by differentiation into RPE cells. Induced PSC-derived RPE cells exhibit ion transport, membrane potential, polarized VEGF secretion and gene expression that is similar to native RPE. Despite having similar in vitro function, morphology, immunostaining and microscopic analysis, it remains to be seen if iPSC-derived RPE can replicate the myriad of in vivo functions, including immunomodulatory effects, of native RPE cells. Historically, adjuvant RPE transplantation during CNV resections were technically difficult and complicated by immune rejection. Autologous iPSCs are hypothesized to reduce the risk of immune rejection, but their production is time-consuming and expensive. Alternatively, allogenic transplantation using human leukocyte antigen (HLA)-matched iPSCs, similar to HLA-matched organ transplantation, is currently being investigated. Expert opinion: Challenges to successful transplantation with iPSCs include surgical technique, a pathologic subretinal microenvironment, possible immune rejection, and complications of immunosuppression.Item Longer-Term Anti-VEGF Therapy Outcomes in Neovascular Age-Related Macular Degeneration, Diabetic Macular Edema, and Vein Occlusion-Related Macular Edema: Clinical Outcomes in 130 247 Eyes(Elsevier, 2022-09) Ciulla, Thomas A.; Hussain, Rehan M.; Taraborelli, Donna; Pollack, John S.; Williams, David F.; Ophthalmology, School of MedicinePurpose The clinical practice visual acuity (VA) outcomes of anti-VEGF therapy for up to 5 years were assessed in patients with neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), branch retinal vein occlusion-related macular edema (BRVO-ME), and central retinal vein occlusion-related macular edema (CRVO-ME). Design A retrospective analysis was performed using the Vestrum Health Retina Database. Participants Treatment-naive patients with nAMD, DME, BRVO-ME, or CRVO-ME who received anti-VEGF injections between 2014 and 2019 and had follow-up data for ≥12 months. Methods Data on age, sex, the number of anti-VEGF treatments, and VA were analyzed. Main Outcome Measures Mean VA change up to 3 years (BRVO-ME and CRVO-ME) and 5 years (nAMD and DME). Results At 1, 3, and 5 years, in 67 666, 21 305, and 5208 eyes with nAMD, after a mean of 7.6, 19.5, and 32 injections, there was a mean change of +3.1, −0.2, and −2.2 letters, respectively. At 1, 3, and 5 years, in 40 832, 7728, and 1192 eyes with DME, after a mean of 6.2, 15.4, and 26.0 injections, there was a mean change of +4.7, +3.3, and +3.1 letters, respectively. At 1 and 3 years, in 12 451 and 3027 eyes with BRVO-ME, after a mean of 7.1 and 18.2 injections, there was a mean change of +9.5 and +7.7 letters, respectively. At 1 and 3 years, in 9298 and 2264 eyes with CRVO-ME, after a mean of 7.3 and 18.8 injections, there was a mean change of +8.3 and +6.0 letters, respectively (P < 0.01 for all VA changes of > 1 letter). In all 4 conditions, the mean VA increased with the mean number of anti-VEGF injections, eyes with a baseline VA of 20/40 or better tended to lose VA, and eyes with progressively worse baseline VA experienced a progressively greater VA gain at 3 years. Conclusions In practice, patients with nAMD, DME, BRVO-ME, and CRVO-ME showed limited visual outcomes, with patients with nAMD tending to lose VA at 3 and 5 years. Across all 4 disorders, the mean change in VA correlated with treatment intensity at 1, 3, and 5 years. Patients with better baseline VA are more vulnerable to vision loss.