Adaptive Optics Images in Clinical Trials of 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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High Resolution Retinal Imaging Based on Ocular Aberration Measurement and Compensation

Applied Mechanics and Materials ◽

10.4028/www.scientific.net/amm.246-247.213 ◽

2012 ◽

Vol 246-247 ◽

pp. 213-218

Author(s):

Chun Liang ◽

Jian Xin Shen ◽

Sai Sai Niu

Keyword(s):

High Resolution ◽

Adaptive Optics ◽

Imaging System ◽

Low Cost ◽

Critical Role ◽

Retinal Imaging ◽

Retinal Disease ◽

Retinal Cell ◽

Wavefront Aberration ◽

Diagnostic Modality

Ocular retinal imaging is a major diagnostic modality for retinal disease, and can play a critical role for diagnosing systemic diseases such as diabetes and eye-specific diseases such as macular degeneration and diabetic retinopathy, the leading causes of blindness. In order to get high-resolution retinal imaging and develop the low-cost and compact retinal imaging system, we employ micro adaptive optics, which is consisted of wavefront sensor, wavefront corrector and control system. In this paper, the theory, design and testing of the ocular retinal microscopy is detailed, with an emphasis on the eye wavefront aberration describing, aberration detecting method with Hartmann-Shack wavefront sensing and close-loop aberration compensating by micromachined membrane deformable mirrors(MMDM).The ocular retinal microscopy experimental setup is built, the retinal cell imaging had been snapped. It is showed in this work that the ocular retinal microscopy based on adaptive optics system can enable diffraction-limited imaging of micro-scale features of the retina, through real-time compensation of aberrations introduced by the eye.

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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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Computer-assisted photoreceptor assessment on Heidelberg Engineering Spectralis™ High Magnification Module™ images

Graefe s Archive for Clinical and Experimental Ophthalmology ◽

10.1007/s00417-021-05326-6 ◽

2021 ◽

Author(s):

Timo W. F. Mulders ◽

B. Jeroen Klevering ◽

Carel B. Hoyng ◽

Thomas Theelen

Keyword(s):

Adaptive Optics ◽

Nearest Neighbor ◽

Retinal Disease ◽

Computer Assisted ◽

High Magnification ◽

Cone Photoreceptor ◽

Friedman Test ◽

The Third ◽

Progression Marker ◽

Cone Density

Abstract Purpose To evaluate reliability and repeatability of computer-assisted measurements of cone photoreceptor metrics on Heidelberg Engineering Spectralis™ High Magnification Module (HMM™) Automatic Real-time Tracking (ART™) images. Methods We analyzed HMM™ images in three separate study arms. Computer-assisted cone identification software was validated using an open-access adaptive optics (AO) dataset. We compared results of the first arm to data from AO and histology. We evaluated intersession repeatability of our computer-assisted cone analysis in the second arm. We assessed the capability of HMM™ to visualize cones in the presence of pathology in the third arm. Results We included 10 healthy subjects in the first arm of our study, 5 additional healthy participants in the second arm and 5 patients in the third arm. In total, we analyzed 225 regions of interest on HMM™ images. We were able to automatically identify cone photoreceptors and assess corresponding metrics at all eccentricities between 2 and 9° from the fovea. Cone density significantly declined with increasing eccentricity (p = 4.890E-26, Friedman test). With increasing eccentricity, we found a significant increase in intercell distance (p = 2.196E-25, Friedman test) and nearest neighbor distance (p = 1.997E-25, Friedman test). Cone hexagonality ranged between 71 and 85%. We found excellent automated intersession repeatability of cone density counts and spacing measurements. In pathology, we were also able to repeatedly visualize photoreceptors. Conclusion Computer-assisted cone photoreceptor analysis on Spectralis™ HMM™ images is feasible, and most cone metrics show excellent repeatability. HMM™ imaging may be useful for photoreceptor analysis as progression marker in outer retinal disease.

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Investigational Neuroprotective Compounds in Clinical Trials for Retinal Disease

Expert Opinion on Investigational Drugs ◽

10.1080/13543784.2021.1896701 ◽

2021 ◽

Author(s):

Daniel Hill ◽

Chiara Compagnoni ◽

M. Francesca Cordeiro

Keyword(s):

Clinical Trials ◽

Retinal Disease

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High-Resolution Imaging with Adaptive Optics and Optical Coherence Tomography, and Functional Changes in Retinal Disease

Journal of Vision ◽

10.1167/7.15.47 ◽

2010 ◽

Vol 7 (15) ◽

pp. 47-47

Author(s):

J. S. Werner ◽

S. S. Choi ◽

R. J. Zawadzki

Keyword(s):

Optical Coherence Tomography ◽

High Resolution ◽

Adaptive Optics ◽

Retinal Disease ◽

High Resolution Imaging ◽

Optical Coherence ◽

Functional Changes ◽

Resolution Imaging

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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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