Leber Hereditary Optic Neuropathy (LHON)

This is a Phase 1/2 repeat-dose, open-label, two-arm, parallel group safety and efficacy study of two doses of VP-001 (30 μg and 75 μg) in participants with confirmed PRPF31 mutation-associated retinal dystrophy, including participants previously treated with VP001 in the PLATYPUS Study or WALLABY Study for a minimum of 8 weeks.

Handheld OCT imaging is an advancement in ophthalmic imaging technology allowing us to image the pediatric retina. lt has tremendous potential to be applied to assess the structure and blood flow of children with retinal vascular diseases or as a screening tool for pediatric retinal diseases. Despite progress in the development of hand-held OCT probes, there remains a critical gap in technology to achieve fast, proper alignment between the imaging device and the infant eye. Even with the most skilled operators, to acquire consistent OCT and OCTA data capture for longitudinal follow up in uncooperative patients at the bedside remains difficult. lmprovements in hand-held OCT probe technology for auto-alignment to the patient's eye, as well as on-line detection of image quality and auto-saving at the proper time, would address this critical gap in handheld OCT technology. Our biomedical engineering team, has developed prior iterations of the handheld OCT devices and successfully imaged the pediatric retina. The goal of the current study is to conduct a pilot study to test a new version of the handheld OCT device capable of auto-alignment to image the retina in adult volunteers, and adult and pediatric patients in clinic. The investigators plan to enroll 20 healthy adult volunteers, 20 adult patients and 10 pediatric patients from the ophthalmology clinic. This is an observational study. There are no known risks associated with handheld OCT imaging and no adverse events identified imaging with prior iterations of handheld OCT devices. lmaging data will be downloaded to a secure server for protocol image processing, segmentation, and analysis per protocol in the Duke Advanced Research in SS/SDOCT lmaging (DARSI) laboratory.

BACKGROUNDS Nowadays, phacoemulsification for cataract treatment is the most common surgical procedure performed and anesthetics procedure has been shifted from retrobulbar or peribulbar anesthesia to topical anesthesia (TA). Phacoemulsification under TA proved to be a safe and low risk procedure with the incidence of adverse events requiring medical emergency team interventions to be 0.04%. However, it is not uncommon that patients can suffer from pain, anxiety and unpleasant visual sensation during this procedure. Complementary sedation has long been thought to alleviate the anxiety and pain of the patient during surgery with local anesthesia. Studies revealed that approximately one fourth of the patients underwent phacoemulsification under TA or retrobulbar anesthesia requested additional intravenous sedation of midazolam. \[8\] However, the intravenous sedation, such as midazolam, propofol, or etomidate, increase the risk of additional anesthetic complications of heart rate, blood pressure, body temperature, and nausea, \[9,10\] and therefore, anesthesia monitoring was mandatory during the surgery. Compared with intravenous sedation, oral sedation is less costly and less invasive. Studies with different oral sedation agents revealed different effects. In the study of 41 patients serving themselves as control, patients reported more pain and photophobia in the surgery with TA alone than the other with midazolam syrup and oral transmucosal fentanyl citrate. However, two studies comparing oral diazepam or triazolam with intravenous midazolam showed similar rates of anxiety and pain or noninferior satisfaction. Moreover, the randomized control trial containing 50 procedures in each groups revealed that patients received TA alone during phacoemulsification reported similar pain or anxiety level to those received complementary intravenous midazolam. Despite the abundant results from above, nearly 40% patients reported moderate to extremely anxiety during phacoemulsification under TA, and approximate 7% of patients rated themselves extreme anxiety or were diagnosed as anxiety. A simple comparison between with or without complementary sedation for general patients underwent phacoemulsification with TA is merely not enough. Further investigations to reduce the anxiety experienced during phacoemulsification with TA according to patients' characteristics is therefore mandatory. Previous studies had showed that patients with higher level of trait anxiety reported higher anxiety response for a stressful situation. Preoperative anxiety levels were also reported to be a significant predictor of pain experience during phacoemulsification with TA. The need for complementary sedation could be different in patients with different trait anxiety. Furthermore, different severity levels of anxiety and pain were experienced during the first and second eye surgery. Therefore, in this study, the investigators will investigate the trait anxiety of patients planned for phacoemulsification under TA and its effect on their anesthetic satisfaction with complementary oral sedation. The investigators will also analysis the anxiety and pain experienced in the first and second eye phacoemulsification in patients with different levels of trait anxiety. The investigators choose alprazolam as the oral sedative. It was reported to have a shorter half-life and less side effects of drowsiness and lightheadedness than diazepam used in previous studies.

The AnovaOS™ Network Powered Patient Registry may be used to inform the development and conduct of clinical trials and observational studies designed to better understand, prevent, diagnose, treat, ameliorate or cure disease. The AnovaOS™ Network Powered Patient Registry may additionally be used to expedite identification and recruitment of participants for clinical trials of promising therapeutics and observational studies.

Objective: This project, Clinical and Molecular Studies in Families with Inherited Eye Disease will study inherited eye diseases, both Mendelian and complex age related inherited eye diseases, in families of many nationalities and ethnic backgrounds in order to identify the genes that, when mutated, cause inherited eye diseases and the pathophysiology through which they act. Among the diseases studied will be cataracts, corneal dystrophies and other corneal diseases, retinal degenerations, myopia and other anterior chamber defects, and glaucoma. Study Population: Families and individuals of many nationalities and ethnic backgrounds. We will study a maximum of 5,000 participants and family members. Design: The study consists of ascertaining individuals and especially families with multiple individuals, affected by both congenital and age related inherited eye diseases. These participants and their families will undergo detailed ophthalmological examinations to characterize their visual system and determine their affectation status. A blood sample will be collected from each individual for isolation of DNA and in some individuals for lymphoblastoid transformation to establish a renewable source of DNA. Linkage analysis, association analysis, physical mapping, and mutational screening will be carried out to identify the specific gene and the mutations in it that are associated with inherited eye disease in the family. Mutation screening may involve Sanger sequencing if a small number of candidate genes are identified, or whole genome or whole exome sequencing if more genes remain as viable candidates after the initial analysis. If necessary, the gene product will be characterized biochemically. Blood samples may also be used to complete analyses such as: hemoglobin A1c (HbA1c), fasting blood glucose, and glucose tolerance tests. The study will enroll participants at NEI and collaborating institutions. Outcome Measures: Linkage will be determined using the lod score method, association will be determined using standard statistical procedures to estimate p values, and mutations in specific genes will be assessed using a combination of residue conservation, blosum score, bioinformatic prediction of structural damage to the protein, and molecular modeling. Assessment of biochemical, metabolic, and physiological effects of these mutations will be individualized to the specific case.

In the diagnostic approach of patients with ophthalmologic diseases, as well as for surgical purposes, the administration of mydriatic and cycloplegic drugs is indispensable. Among these, the combination of tropicamide and phenylephrine (TF) is commonly used. Studies evaluating the topical ocular administration of these medications have demonstrated an adequate risk-benefit balance; however, certain local and systemic safety aspects remain insufficiently evaluated. Justification: This study will help identify the at-risk population (clinical determinants) prior to the administration of drugs such as TF, provide additional information regarding the safety profile of this drug at the 8 mg/50 mg/mL concentration, and propose measures to reduce the occurrence of adverse drug reactions (ADRs) in at-risk populations. It also aims to develop safety barriers that allow for safer administration of the medication. Moreover, this research provides a first approximation and establishes the basis for future studies that may compare different TF concentrations. Hypothesis: There will be a positive association between clinical determinants and the occurrence of adverse drug reactions. Research Question: Is there an association between the clinical determinants of hospitalized patients and the occurrence of adverse drug reactions following the administration of tropicamide/phenylephrine? Objective: To evaluate the association between clinical determinants and the occurrence of adverse drug reactions in hospitalized patients who received tropicamide/phenylephrine 8 mg/50 mg/mL. Materials and Methods: An ambispective study will be conducted to identify ADRs associated with TF administration, as well as to characterize pathologies that may predispose patients to ADRs (clinical determinants, CD), through the use of a questionnaire, with the purpose of establishing an association between them. Data Analysis: Results will be analyzed using the Chi-square test for qualitative variables and the calculation of odds ratios (OR) with 95% confidence intervals. Quantitative variables will be analyzed using the Student's t-test for normally distributed data, or the Wilcoxon signed-rank test for data not normally distributed. Normality will be assessed with the Kolmogorov-Smirnov test (p \> 0.05). The association between CDs and ADRs will be evaluated through logistic regression analysis

Visual impairment is one of the ten most prevalent disabilities and poses extraordinary challenges to individuals in our society, which is heavily dependent on sight. Drug development and genetic engineering have had only marginal success as possible treatments but new hope has been generated by recent advances in neuroscience, micro-fabrication technologies, biomaterials, neuromorphic engineering and information and communication technologies leading to the development of highly sophisticated neural prosthetic devices which interact with the nervous system. Such assistive devices have already allowed thousands of deaf patients to hear sounds and acquire language abilities and the same hope exists in the field of visual rehabilitation. Several research groups worldwide are engaged in attempts to restore vision through retinal prosthesis. However these devices are not viable for all causes of blindness. Thus, if the communication link between eye and brain is destroyed (e.g. for Glaucoma or optic nerve atrophy), as is the case for 148 million people worldwide, then visual cortical prosthesis holds the dominant hope for visual restoration. Consequently, there are many compelling reasons to pursue the development of a cortical prosthesis capable of restoring some useful vision in profoundly blind patients and this approach may be the only treatment available for end-stage retinitis pigmentosa patients and for pathologies such as glaucoma optic atrophy, trauma to the retina and/or optic nerves, and for diseases of the central visual pathways due to brain injuries or stroke. The investigators will implant the CORTIVIS vision neuroprosthetic system, which utilizes a FDA cleared microelectrode array, into blind human volunteers and obtain descriptive feedback about visualized percepts. The experiments are designed to learn if volunteers can learn to integrate the electrical stimulation of brain visual areas into meaningful percepts. It is expected that a cortical device can create truly meaningful visual percepts that can be translated into functional gains such as the recognition, localization and grasping of objects or skillful navigation in familiar an unfamiliar environments resulting in a substantial improvement in the standard of living of blind and visually impaired persons. All the experiments will be carried out at the patient's hospital room (Hospital IMED Elche) during the post-surgical period or in a human psychophysical laboratory (University Miguel Hernández).

This is a concurrent open-label study for patients who are deemed safe to participate in the electrical stimulation trial but do not fit the exact criteria for the randomized clinical trial.

Part 1: Dose-Finding At the dose-finding part, the principle is that the Safety Review Committee (SRC) will determine whether to make dose adjustment based on the safety data of the starting dose in Part 1. The recommended dose (safe and effective dose) of the Part 2 study will be determined jointly by the SRC, IDMC, sponsor and the drug regulatory authority after the interim analysis in Part 1 is completed. The starting dose in Part 1 is 1.5 × 109 vg, 0.05 mL eye/dose. The safety of the starting dose will be reviewed by the SRC and the dose escalation or de-escalation will be recommended by the SRC. The safety of the starting dose will first be performed in 6 evaluable subjects. Part 2 (including the safety run-in phase and the randomized, double-blind and sham-injection control study): First Stage: safety run-in phase: The safety run-in phase of Part 2 will enroll 6 evaluable subjects (including at least 1 minor subject aged ≥ 12 years and \< 18 years) aged ≥ 12 years and ≤ 75 years at the dose determined in Part 1, namely 4.5 x 109 vg, 0.05 mL eye/dose (high dose) and monitor the safety for at least 6 weeks. If there is no new safety concern evaluated by the SRC, the randomized, double-blind, sham-injection control study can be initiated. Second Stage: randomized, double-blind, sham-injection control study: The randomized, double-blind, sham-injection control study of Part 2 is to verify the efficacy and safety of NR082 in LHON caused by mitochondrial gene ND4 mutation at the dose determined in Part 1 of the study, namely 4.5 x 109 vg, 0.05 mL eye/dose (high dose). This part is divided into the NR082 treatment group and the control group (sham-injection group).

OBJECTIVE: Molecular genetics and genomics are revolutionizing the delivery of medicine in general and ophthalmology in particular. New treatment and prevention strategies rely on a detailed understanding of the genetics and molecular pathogenesis of vision-threatening disease. In addition, in order to determine whether an intervention is therapeutic, we must first have some understanding of what the best clinical outcome variables are for measuring a treatment effect. Because our ultimate goal is to develop disease-specific protocols for specific inherited conditions, establishing this protocol will help us establish an initial critical mass of patients and of knowledge to write such protocols; as such, this protocol will be hypothesis generating. A secondary aim of this protocol is to provide a mechanism for obtaining research samples from subjects that may be used for laboratory investigations; in this case, the basic research may be both hypothesis generating and/or hypothesis testing. Lastly, the Ophthalmic Genetics Branch, as a leader in the field and a sponsor of a clinical training program, should have the ability to serve as a tertiary referral center for the nation in the area of undiagnosed genetic eye diseases. STUDY POPULATION: One thousand one hundred (1100) individuals with inherited eye diseases and 400 healthy volunteers (the unaffected relatives of affected participants) will be enrolled. DESIGN: This is a combined evaluation/treatment protocol and a genetic repository study. In general, participants will undergo a complete, age-appropriate, baseline examination and may provide a blood or saliva sample. Some participants may undergo more specialized ophthalmic and/or systemic testing, if clinically indicated by the investigator. Data and specimens generated through clinical care procedures may be collected and analyzed. The data and images obtained from these tests may be used for determining eligibility into another NEI protocol. Additionally, the collection of these data will help meet the primary research objectives of this study. Participants may be asked to complete optional participant reported outcome (PRO) questionnaires which will be assigned based on current diagnosis and previous testing. In a small number of cases, collection of blood, readily available biospecimens and body fluids (e.g., urine, saliva, tear fluid, stool, hair or cheek swab samples), conjunctival swab or lacrimal gland biopsy, impression cytology, and/or a punch skin biopsy may also be performed for research purposes. OUTCOME MEASURES: Given the breadth of ages and disease processes covered under this protocol, we will not systematically obtain any single outcome variable beyond visual acuity on research subjects. However, detailed, disease-specific findings will be collected through the NEI electronic medical record. Findings from systemic testing and from outside exams may be tabulated in a separate, secure database in the laboratory of the Principal Investigator (PI).