Optometry and Vision Sciences - Research Publications

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Ocular development after highly effective modulator treatment early in life.

Zhu, Y ; Li, D ; Reyes-Ortega, F ; Chinnery, HR ; Schneider-Futschik, EK (Frontiers Media SA, 2023)

Highly effective cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulator therapies (HEMT), including elexacaftor-tezacaftor-ivacaftor, correct the underlying molecular defect causing CF. HEMT decreases general symptom burden by improving clinical metrics and quality of life for most people with CF (PwCF) with eligible CFTR variants. This has resulted in more pregnancies in women living with CF. All HEMT are known to be able pass through the placenta and into breast milk in mothers who continue on this therapy while pregnant and breast feeding. Toxicity studies of HEMT in young rats demonstrated infant cataracts, and case reports have reported the presence of congenital cataracts in early life exposure to HEMT. This article reviews the evidence for how HEMT influences the dynamic and interdependent processes of healthy and abnormal lens development in the context of HEMT exposure during pregnancy and breastfeeding, and raises questions that remain unanswered.
Awareness of Usher Syndrome and the Need for Multidisciplinary Care: A Cross-Occupational Survey of Allied Health Clinicians

Ayton, LN ; Galvin, KL ; Johansen, L ; O'Hare, F ; Shepard, ER (DOVE MEDICAL PRESS LTD, 2023)

BACKGROUND: Usher syndrome is the most common cause of deaf-blindness, affecting up to 1 in 6000 people. Multidisciplinary care is required to maximize outcomes for individuals and families. This study assessed awareness of Usher Syndrome amongst allied health clinicians who provide care related to the primarily affected senses of hearing and vision, ie, optometry, orthoptics and audiology. METHODS: A prospective cross-sectional online survey of clinicians working in Australian university-affiliated clinics (7 optometry, 1 orthoptics and 4 audiology) was completed between September 2021 and January 2022. Questions were asked about the cause, common symptoms, and awareness of health professions who manage Usher syndrome. RESULTS: The 27 audiologists, 40 optometrists, and 7 orthoptists who completed the survey included 53 females (71.6%), had an average age of 37 years (range 24-70), and had an average duration of clinical experience of 13 years (range 1-45 years). The majority of respondents correctly identified Usher syndrome as a genetic condition (86%), identified at least two of the affected senses (97%), and identified the progressive nature of the vision and hearing losses (>90%). Awareness of vestibular dysfunction and its characteristics was low, as was knowledge of the key treatment roles that speech pathologists, genetic counsellors and geneticists play in the management of Usher Syndrome. The majority of respondents also did not identify important aspects of care within their own discipline. CONCLUSION: This study has shown that there is a need for targeted education to be delivered to hearing and vision care allied health clinicians to raise awareness of the vestibular impacts and aspects of vision loss experienced by people with Usher syndrome. This education needs to target the broad range of clinicians who have a key role in providing multidisciplinary care (including speech pathologists, geneticists, and genetic counsellors) and to identify the key aspects of good-quality multidisciplinary care.
Mapping the human parafoveal vascular network to understand flow variability in capillaries.

Neriyanuri, S ; Bedggood, P ; Symons, RCA ; Metha, A ; Grulkowski, I (Public Library of Science (PLoS), 2023)

Capillary flow is known to be non-homogenous between vessels and variable over time, for reasons that are poorly understood. The local properties of individual vessels have been shown to have limited explanatory power in this regard. This exploratory study investigates the association of network-level properties such as vessel depth, branch order, and distance from the feeding arteriole with capillary flow. Detailed network connectivity analysis was undertaken in 3 healthy young subjects using flood-illuminated adaptive optics retinal imaging, with axial depth of vessels determined via optical coherence tomography angiography. Forty-one out of 70 vessels studied were of terminal capillary type, i.e. fed from an arterial junction and drained by a venous junction. Approximately half of vessel junctions were amenable to fitting with a model of relative branch diameters, with only a few adhering to Murray's Law. A key parameter of the model (the junction exponent) was found to be inversely related to the average velocity (r = -0.59, p = 0.015) and trough velocity (r = -0.67, p = 0.004) in downstream vessels. Aspects of cellular flow, such as the minimum velocity, were also moderately correlated (r = 0.46, p = 0.009) with distance to the upstream feeding arteriole. Overall, this study shows that capillary network topology contributes significantly to the flow variability in retinal capillaries in human eyes. Understanding the heterogeneity in capillary flow is an important first step before pathological flow states can be properly understood. These results show that flow within capillary vessels is not affected by vessel depths but significantly influenced by the upstream feeder distance as well as the downstream vessel junction exponents, but there remains much to be uncovered regarding healthy capillary flow.
Preexisting immunity restricts mucosal antibody recognition of SARS-CoV-2 and Fc profiles during breakthrough infections

Selva, KJ ; Ramanathan, P ; Haycroft, ER ; Reynaldi, A ; Cromer, D ; Tan, CW ; Wang, L-F ; Wines, BD ; Hogarth, PM ; Downie, LE ; Davis, SK ; Purcell, RA ; Kent, HE ; Juno, JA ; Wheatley, AK ; Davenport, MP ; Kent, SJ ; Chung, AW (AMER SOC CLINICAL INVESTIGATION INC, 2023-09-22)

Understanding mucosal antibody responses from SARS-CoV-2 infection and/or vaccination is crucial to develop strategies for longer term immunity, especially against emerging viral variants. We profiled serial paired mucosal and plasma antibodies from COVID-19 vaccinated only vaccinees (vaccinated, uninfected), COVID-19-recovered vaccinees (recovered, vaccinated), and individuals with breakthrough Delta or Omicron BA.2 infections (vaccinated, infected). Saliva from COVID-19-recovered vaccinees displayed improved antibody-neutralizing activity, Fcγ receptor (FcγR) engagement, and IgA levels compared with COVID-19-uninfected vaccinees. Furthermore, repeated mRNA vaccination boosted SARS-CoV-2-specific IgG2 and IgG4 responses in both mucosa biofluids (saliva and tears) and plasma; however, these rises only negatively correlated with FcγR engagement in plasma. IgG and FcγR engagement, but not IgA, responses to breakthrough COVID-19 variants were dampened and narrowed by increased preexisting vaccine-induced immunity against the ancestral strain. Salivary antibodies delayed initiation following breakthrough COVID-19 infection, especially Omicron BA.2, but rose rapidly thereafter. Importantly, salivary antibody FcγR engagements were enhanced following breakthrough infections. Our data highlight how preexisting immunity shapes mucosal SARS-CoV-2-specific antibody responses and has implications for long-term protection from COVID-19.
Genetic testing and gene therapy in retinal diseases: Knowledge and perceptions of optometrists in Australia and New Zealand

Britten-Jones, AC ; Mack, HGG ; Vincent, ALL ; Hill, LJJ ; Edwards, TLL ; Ayton, LNN (WILEY, 2023-08-08)

With advances in gene-based therapies for heritable retinal diseases, primary eye care clinicians should be informed on ocular genetics topics. This cross-sectional survey evaluated knowledge, attitudes, and concerns regarding genetic testing and gene therapy for retinal diseases among optometrists in Australia and New Zealand. Survey data included practitioner background, attitudes and practices towards genetic testing for monogenic inherited retinal disease (IRDs) and age-related macular degeneration, and knowledge of ocular genetics and gene therapy. Responses were received from 516 optometrists between 1 April and 31 December 2022. Key perceived barriers to accessing genetic testing were lack of clarity on referral pathways (81%), cost (65%), and lack of treatment options if a genetic cause is identified (50%). Almost all respondents (98%) believed that ophthalmologists should initiate genetic testing for IRDs and fewer understood the role of genetic counsellors and clinical geneticists. This study found that optometrists in Australia and New Zealand have a high level of interest in ocular genetics topics. However, knowledge gaps include referral pathways and awareness of genetic testing and gene therapy outcomes. Addressing perceived barriers to access and promoting sharing of knowledge between interdisciplinary networks can set the foundation for genetic education agendas in primary eye care.
Perspectives of carriers of X-linked retinal diseases on genetic testing and gene therapy: A global survey

Gocuk, SA ; Edwards, TL ; Jolly, JK ; Ayton, LN (WILEY, 2023-10-20)

Female carriers of X-linked inherited retinal diseases (IRDs) are burdened with potentially passing their disease-causing variant to future generations, as well as exhibiting signs of retinal disease themselves. This study aimed to investigate carriers' experiences of genetic testing, emotions relating to having affected children, and their knowledge regarding genetic testing and gene therapy. An online survey was advertised to self-identified carriers worldwide. Two hundred and twenty-eight carriers completed the survey with mean age of 51 years (SD ± 15.0). A majority of respondents resided in the United States of America (51%), Australia (19%), and the United Kingdom (14%). Most carriers identified with feelings of guilt (70%), concern (91%), and anxiety (88%) for their child. Female carriers who had given birth to children had significantly greater gene therapy knowledge compared to carriers who had not (p < 0.05). Respondents agreed that their eyecare provider and general practitioner helped them understand their condition (63%), however, few carriers reported receiving psychological counselling (9%) or family planning advice (5%). Most respondents (78%) agreed that gene therapy should be available to carriers. This study emphasises the importance of providing appropriate counselling to female carriers and illustrates the motivation of many to participate in emerging treatment options, such as gene therapy.
Mucosal antibody responses following Vaxzevria vaccination

Selva, KJ ; Ramanathan, P ; Haycroft, ER ; Tan, CW ; Wang, L-F ; Downie, LE ; Davis, SK ; Purcell, RA ; Kent, HE ; Juno, JA ; Wheatley, AK ; Davenport, MP ; Kent, SJ ; Chung, AW (WILEY, 2023)

Mucosal antibodies play a key role in protection against breakthrough COVID-19 infections and emerging viral variants. Intramuscular adenovirus-based vaccination (Vaxzevria) only weakly induces nasal IgG and IgA responses, unless vaccinees have been previously infected. However, little is known about how Vaxzevria vaccination impacts the ability of mucosal antibodies to induce Fc responses, particularly against SARS-CoV-2 variants of concern (VoCs). Here, we profiled paired mucosal (saliva, tears) and plasma antibodies from COVID-19 vaccinated only vaccinees (uninfected, vaccinated) and COVID-19 recovered vaccinees (COVID-19 recovered, vaccinated) who both received Vaxzevria vaccines. SARS-CoV-2 ancestral-specific IgG antibodies capable of engaging FcγR3a were significantly higher in the mucosal samples of COVID-19 recovered Vaxzevria vaccinees in comparison with vaccinated only vaccinees. However, when IgG and FcγR3a engaging antibodies were tested against a panel of SARS-CoV-2 VoCs, the responses were ancestral-centric with weaker recognition of Omicron strains observed. In contrast, salivary IgA, but not plasma IgA, from Vaxzevria vaccinees displayed broad cross-reactivity across all SARS-CoV-2 VoCs tested. Our data highlight that while intramuscular Vaxzevria vaccination can enhance mucosal antibodies responses in COVID-19 recovered vaccinees, restrictions by ancestral-centric bias may have implications for COVID-19 protection. However, highly cross-reactive mucosal IgA could be key in addressing these gaps in mucosal immunity and may be an important focus of future SARS-CoV-2 vaccine development.
Characterising the diagnosis of genetic maculopathies in a real-world private tertiary retinal practice in Australia: protocol for a retrospective clinical audit

Britten-Jones, AC ; Markakis, D ; Guymer, RH ; Lin, M-L ; Skalicky, S ; Ayton, LN ; Mack, HG (TAYLOR & FRANCIS LTD, 2023-12-12)

PURPOSE: Accurate diagnosis of macular atrophy is paramount to enable appropriate treatment when novel treatments for geographic atrophy and macular dystrophies become available. Genetic testing is useful in distinguishing between the two conditions but is not feasible for the majority of patients in real-world clinical practice. Therefore, we aimed to investigate the potential misdiagnosis of inherited macular dystrophy as age-related macular degeneration (AMD) in real-world ophthalmic practice to assist in the development of guidelines to improve diagnostic accuracy while minimizing genetic testing for targeted patients. METHODS: Retrospective review of the medical records of patients diagnosed with AMD, which included imaging, between 1995 and 2023 from a large multidisciplinary private ophthalmic practice in Australia. We will use a stepwise method to screen for probable cases of macular dystrophy, followed by a consensus review by an expert panel. The outcomes are (1) to determine the potential misdiagnosis rate of macular dystrophy as atrophic AMD by retinal specialists and general ophthalmologists; (2) to identify clinical imaging modalities that are most useful for differentiating macular dystrophy from atrophic AMD; and (3) to establish preliminary guidance for clinicians to improve the diagnosis of macular atrophy from AMD in practice, and thereby target cost-efficient genetic testing. DISCUSSION: Improving the diagnostic accuracy of both AMD and macular dystrophy, while ensuring cost-efficient genetic testing, will improve the targeted treatment of macular diseases when emerging treatments become available.
Redefining the human corneal immune compartment using dynamic intravital imaging

Downie, LE ; Zhang, X ; Wu, M ; Karunaratne, S ; Loi, JK ; Senthil, K ; Arshad, S ; Bertram, K ; Cunningham, AL ; Carnt, N ; Mueller, SN ; Chinnery, HR (NATL ACAD SCIENCES, 2023-08-01)

The healthy human cornea is a uniquely transparent sensory tissue where immune responses are tightly controlled to preserve vision. The cornea contains immune cells that are widely presumed to be intraepithelial dendritic cells (DCs). Corneal immune cells have diverse cellular morphologies and morphological alterations are used as a marker of inflammation and injury. Based on our imaging of corneal T cells in mice, we hypothesized that many human corneal immune cells commonly defined as DCs are intraepithelial lymphocytes (IELs). To investigate this, we developed functional in vivo confocal microscopy (Fun-IVCM) to investigate cell dynamics in the human corneal epithelium and stroma. We show that many immune cells resident in the healthy human cornea are T cells. These corneal IELs are characterized by rapid, persistent motility and interact with corneal DCs and sensory nerves. Imaging deeper into the corneal stroma, we show that crawling macrophages and rare motile T cells patrol the tissue. Furthermore, we identify altered immune cell behaviors in response to short-term contact lens wear (acute inflammatory stimulus), as well as in individuals with allergy (chronic inflammatory stimulus) that was modulated by therapeutic intervention. These findings redefine current understanding of immune cell subsets in the human cornea and reveal how resident corneal immune cells respond and adapt to chronic and acute stimuli.
Adaptive optics imaging in inherited retinal diseases: A scoping review of the clinical literature.

Britten-Jones, AC ; Thai, L ; Flanagan, JPM ; Bedggood, PA ; Edwards, TL ; Metha, AB ; Ayton, LN (Elsevier BV, 2023-09-29)

Adaptive optics (AO) imaging enables direct, objective assessments of retinal cells. Applications of AO show great promise in advancing our understanding of the etiology of inherited retinal disease (IRDs) and discovering new imaging biomarkers. This scoping review systematically identifies and summarizes clinical studies evaluating AO imaging in IRDs. Ovid MEDLINE and EMBASE were searched on February 6, 2023. Studies describing AO imaging in monogenic IRDs were included. Study screening and data extraction were performed by 2 reviewers independently. This review presents (1) a broad overview of the dominant areas of research; (2) a summary of IRD characteristics revealed by AO imaging; and (3) a discussion of methodological considerations relating to AO imaging in IRDs. From 140 studies with AO outcomes, including 2 following subretinal gene therapy treatments, 75% included fewer than 10 participants with AO imaging data. Of 100 studies that included participants' genetic diagnoses, the most common IRD genes with AO outcomes are CNGA3, CNGB3, CHM, USH2A, and ABCA4. Confocal reflectance AO scanning laser ophthalmoscopy was the most reported imaging modality, followed by flood-illuminated AO and split-detector AO. The most common outcome was cone density, reported quantitatively in 56% of studies. Future research areas include guidelines to reduce variability in the reporting of AO methodology and a focus on functional AO techniques to guide the development of therapeutic interventions.

Optometry and Vision Sciences - Research Publications

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