Investigational Neuroprotective Compounds in Clinical Trials for Retinal Disease

Mutations affecting the Retinitis Pigmentosa GTPase Regulator (RPGR) gene are the commonest cause of X-linked and recessive retinitis pigmentosa (RP), accounting for 10%–20% of all cases of RP. The phenotype is one of the most severe amongst all causes of RP, characteristic for its early onset and rapid progression to blindness in young people. At present there is no cure for RPGR-related retinal disease. Recently, however, there have been important advances in RPGR research from bench to bedside that increased our understanding of RPGR function and led to the development of potential therapies, including the progress of adeno-associated viral (AAV)-mediated gene replacement therapy into clinical trials. This manuscript discusses the advances in molecular research, which have connected the RPGR protein with an important post-translational modification, known as glutamylation, that is essential for its optimal function as a key regulator of photoreceptor ciliary transport. In addition, we review key pre-clinical research that addressed challenges encountered during development of therapeutic vectors caused by high infidelity of the RPGR genomic sequence. Finally, we discuss the structure of three current phase I/II clinical trials based on three AAV vectors and RPGR sequences and link the rationale behind the use of the different vectors back to the bench research that led to their development.

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Perspectives of people with inherited retinal diseases on ocular gene therapy in Australia: protocol for a national survey

BMJ Open ◽

10.1136/bmjopen-2020-048361 ◽

2021 ◽

Vol 11 (6) ◽

pp. e048361

Author(s):

Heather G Mack ◽

Fred K Chen ◽

John Grigg ◽

Robyn Jamieson ◽

John De Roach ◽

...

Keyword(s):

Quality Of Life ◽

Gene Therapy ◽

Clinical Trials ◽

Support Groups ◽

Retinal Dystrophy ◽

Retinal Disease ◽

Related Quality ◽

Biallelic Mutations ◽

The University

IntroductionVoretigene neparvovec-rzyl (Luxturna) was approved by the Australian Therapeutic Goods Administration on 4 August 2020 for the treatment of biallelic mutations in the RPE65 gene, a rare cause of congenital and adult-onset retinal dystrophy (predominantly Leber congenital amaurosis). Previous studies have shown that individuals who might participate in gene therapy trials overestimate clinical effect and underestimate risks. However, little is known about the perspectives of patients who may be offered approved gene therapy treatment for ocular conditions (as distinct from participating in clinical trials of gene therapy). The main objective of this study is to develop a tool to assess knowledge, attitudes and perceptions of approved and future genetic therapies among potential recipients of ocular gene therapy. In addition, we aim to assess the quality of life, attitudes towards clinical trials and vision-related quality of life among this cohort.Methods and analysisA new ‘Attitudes to Gene Therapy for the Eye’ tool will be developed following consultation with people with inherited retinal disease (IRD) and content matter experts. Australians with IRD or their guardians will be asked to complete an internet-based survey comprising existing quality of life and visual function instruments and items for the newly proposed tool. We expect to recruit 500 survey participants from patient support groups, the practices of Australian ophthalmologists who are specialists in IRD and Australian ophthalmic research institutions. Launch is anticipated early 2021. Responses will be analysed using item response theory methodology.Ethics and disseminationThis study has received ethics approval from the University of Melbourne (#2057534). The results of the study will be published in a peer-reviewed journal and will be presented at relevant conferences. Organisations involved in recruitment, and the Patient Engagement Advisory committee will assist the research team with dissemination of the study outcomes.

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Adaptive Optics Images in Clinical Trials of Retinal Disease

Journal of Vision ◽

10.1167/19.8.24 ◽

2019 ◽

Vol 19 (8) ◽

pp. 24

Author(s):

Jacque Duncan

Keyword(s):

Clinical Trials ◽

Adaptive Optics ◽

Retinal Disease

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Adaptive Optics for inherited retinal disease clinical trials

Acta Ophthalmologica ◽

10.1111/aos.13972_311 ◽

2018 ◽

Vol 96 (S261) ◽

pp. 84-84

Keyword(s):

Clinical Trials ◽

Adaptive Optics ◽

Retinal Disease ◽

Inherited Retinal Disease

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Functional evaluation in inherited retinal disease

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2021-319994 ◽

2021 ◽

pp. bjophthalmol-2021-319994

Author(s):

Malena Daich Varela ◽

Michalis Georgiou ◽

Shaima A Hashem ◽

Richard G Weleber ◽

Michel Michaelides

Keyword(s):

Clinical Trials ◽

Primary Outcome ◽

Retinal Disease ◽

Functional Evaluation ◽

Retinal Diseases ◽

Full Field ◽

Inherited Retinal Disease ◽

Wide Range ◽

Functional Assessments ◽

Field Static

Functional assessments are a fundamental part of the clinical evaluation of patients with inherited retinal diseases (IRDs). Their importance and impact have become increasingly notable, given the significant breadth and number of clinical trials and studies investigating multiple avenues of intervention across a wide range of IRDs, including gene, pharmacological and cellular therapies. Moreover, the fact that many clinical trials are reporting improvements in vision, rather than the previously anticipated structural stability/slowing of degeneration, makes functional evaluation of primary relevance. In this review, we will describe a range of methods employed to characterise retinal function and functional vision, beginning with tests variably included in the clinic, such as visual acuity, electrophysiological assessment and colour discrimination, and then discussing assessments often reserved for clinical trials/research studies such as photoaversion testing, full-field static perimetry and microperimetry, and vision-guided mobility testing; addressing perimetry in greatest detail, given it is commonly a primary outcome metric. We will focus on how these tests can help diagnose and monitor particular genotypes, also noting their limitations/challenges and exploring analytical methodologies for better exploiting functional measurements, as well as how they facilitate patient inclusion and stratification in clinical trials and serve as outcome measures.

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Validation of electronic visual acuity (EVA) measurement against standardised ETDRS charts in patients with visual field loss from inherited retinal degenerations

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2019-315124 ◽

2019 ◽

Vol 104 (7) ◽

pp. 924-931

Author(s):

Jasleen K Jolly ◽

Kristin Juenemann ◽

Heather Boagey ◽

Marie Nadsady ◽

Holly Bridge ◽

...

Keyword(s):

Clinical Trials ◽

Visual Acuity ◽

Visual Field ◽

Precise Measurement ◽

Visual Field Loss ◽

Retinal Disease ◽

Single Line ◽

Central Vision ◽

Retinal Degenerations ◽

The Us

BackgroundWith the increase in clinical trials testing therapy for retinal disease, there is a need to ensure that outcome measures are both accurate and standardised. The US Food and Drug Administration favours the use of visual acuity measured using ETDRS logMAR charts. The loss of visual field can interfere with visual tracking across the charts, leading to increased variability of measurements. Electronic visual acuity (EVA) presents the optotype on the centre of a screen, thereby removing the tracking element of the task, and may provide a more precise measurement.MethodsVisual acuity was measured twice using ETDRS charts, EVA automated single letter (E-ETDRS) and EVA single line (EVA-SL) presentation (EMMES). Patients underwent microperimetry (MAIA; Centervue) to determine visual field. We tested 65 patients with rod-cone dystrophies and 41 healthy volunteers.ResultsBoth participant groups read 2–3 letters more on average on the electronic charts compared with ETDRS. Limits of agreement using a modified Bland-Altman analysis account for replicates were wider in eyes with foveal defects (−9 to 18) compared with eyes without foveal defects (−11 to 15). Electronic charts in the presence of foveal defects reduced the range (−11 to 13).ConclusionEVA may provide more accurate measures of visual acuity than traditional ETDRS charts in patients when the visual field loss encroached on the central vision. Electronic presentation with a single line of letters was the favoured style reported by patients and should be considered in future interventional clinical trials.

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Trial Interventions in ABCA4- Retinopathy

10.14293/s2199-1006.1.sor-.ppz0nmp.v1 ◽

2020 ◽

Author(s):

Majid Al Breiki

Keyword(s):

Clinical Trials ◽

Literature Review ◽

Visual Impairment ◽

Retinal Disease ◽

Retinal Diseases ◽

Research Opportunities ◽

Treatment Trials ◽

Inherited Retinal Disease ◽

Intervention Trials ◽

The Moment

Abstract: Inherited retinal diseases collectively are one of the leading causes of visual impairment worldwide. ABCA4 retinopathy is the most common inherited retinal disease. In the last few years, there are many advances in the understanding of this disease, which led to many interventional trials with promising results at the moment. This paper is going to present a brief background up to date knowledge in the context of the disease pathophysiology, the main mechanisms involved in this disease and related diseases, and different approaches of the intervention trials. I will be using a literature review to highlight the main structural, physiological, chemical, functional characteristics of ABCA4 transporter physiology. This will be followed by a brief discussion about pathophysiology. Next, analysing, extracting and comparing different interventional options and presenting the current clinical trials for each will be done. This paper expected to discusses and rationally compare between different treatment trials approaches their advantages over others and challenges. A sensible, possible application from current trials from different diseases with similar pathogenesis and possible research opportunities will be discussed.

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Localization of Gallium-67 in Peritoneal Cells by Electron Microscopic Autoradiography

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100072460 ◽

1973 ◽

Vol 31 ◽

pp. 404-405

Author(s):

D. C. Swartzendruber ◽

Norma L. Idoyaga-Vargas

Keyword(s):

Clinical Trials ◽

Soft Tissue ◽

Tumor Tissue ◽

Soft Tissue Tumors ◽

Clinical Usefulness ◽

Electron Microscopic ◽

Normal Cells ◽

Electron Microscopic Autoradiography ◽

Peritoneal Cells ◽

Gallium 67

The radionuclide gallium-67 (67Ga) localizes preferentially but not specifically in many human and experimental soft-tissue tumors. Because of this localization, 67Ga is used in clinical trials to detect humar. cancers by external scintiscanning methods. However, the fact that 67Ga does not localize specifically in tumors requires for its eventual clinical usefulness a fuller understanding of the mechanisms that control its deposition in both malignant and normal cells. We have previously reported that 67Ga localizes in lysosomal-like bodies, notably, although not exclusively, in macrophages of the spocytaneous AKR thymoma. Further studies on the uptake of 67Ga by macrophages are needed to determine whether there are factors related to malignancy that might alter the localization of 67Ga in these cells and thus provide clues to discovering the mechanism of 67Ga localization in tumor tissue.

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