Treatment-Emergent Adverse Events in Gene Therapy Trials for Inherited Retinal Diseases: A Narrative Review

Nuzbrokh, Yan; Kassotis, Alexis; Ragi, Sara D; Jauregui, Ruben; Tsang, Stephen H.

doi:10.1007/s40123-020-00287-1

Cited by 22 publications

(21 citation statements)

References 122 publications

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“…Indeed, the first approved human AAV gene therapy (Luxturna) is for the treatment of an inherited retinal disease, Leber congenital amaurosis. While systemic delivery of AAV vectors has proved more challenging and recently resulted in the tragic deaths of trial participants ( Wilson and Flotte, 2020 ), their use in the eye has been shown to cause minimal adverse events in clinical trials ( Nuzbrokh et al, 2020 ). While lentiviral vectors can struggle to achieve good transduction efficiency and with transgene expression typically only observed around the site of injection ( Balaggan and Ali, 2012 ; Puppo et al, 2014 ), AAV delivery can achieve transduction patterns exceeding the area of the bleb ( Boye et al, 2016 ; Yiu et al, 2020 ).…”

Section: Cell-specific Targeting In the Degenerate Retinamentioning

confidence: 99%

Optogenetic Gene Therapy for the Degenerate Retina: Recent Advances

et al. 2020

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The degeneration of light-detecting rod and cone photoreceptors in the human retina leads to severe visual impairment and ultimately legal blindness in millions of people worldwide. Multiple therapeutic options at different stages of degeneration are being explored but the majority of ongoing clinical trials involve adeno-associated viral (AAV) vector-based gene supplementation strategies for select forms of inherited retinal disease. Over 300 genes are associated with inherited retinal degenerations and only a small proportion of these will be suitable for gene replacement therapy. However, while the origins of disease may vary, there are considerable similarities in the physiological changes that occur in the retina. When early therapeutic intervention is not possible and patients suffer loss of photoreceptor cells but maintain remaining layers of cells in the neural retina, there is an opportunity for a universal gene therapy approach that can be applied regardless of the genetic origin of disease. Optogenetic therapy offers such a strategy by aiming to restore vision though the provision of light-sensitive molecules to surviving cell types of the retina that enable light perception through the residual neurons. Here we review the recent progress in attempts to restore visual function to the degenerate retina using optogenetic therapy. We focus on multiple pre-clinical models used in optogenetic strategies, discuss their strengths and limitations, and highlight considerations including vector and transgene designs that have advanced the field into two ongoing clinical trials.

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Section: Cell-specific Targeting In the Degenerate Retinamentioning

confidence: 99%

Optogenetic Gene Therapy for the Degenerate Retina: Recent Advances

et al. 2020

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“…Various therapeutic strategies for IRDs are currently under development with an increasing research interest in this field [15,16]. However, any therapy would be promising only when the remaining neural retina is preserved.…”

Section: Introductionmentioning

confidence: 99%

Linking the Presence of Macular Oedema to Structural and Functional Alterations in Retinitis Pigmentosa

Friesacher

Torres

Valmaggia

et al. 2021

Klin Monbl Augenheilkd

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Objective To investigate the association between the central retinal thickness (CRT), the retinal nerve fibre layer thickness (RNFL), and the functional alterations in retinitis pigmentosa (RP) patients. Methods Forty-three patients with typical RP and nineteen age-matched controls, who underwent SD-OCT (macular and optic disc OCT protocols) and electrophysiology, were included. The RP group was divided into two subgroups: with clinical appearance of macular oedema (ME-RP; 30 eyes) and without macular oedema (no-ME; 44 eyes). Central retinal thickness OCT data were averaged in three zones (zone 1 [0°–3°], zone 2 [3°–8°], and zone 3 [8°–15°]) and were evaluated in relation to the RNFL thickness and electrophysiological data. Results The ME-RP group showed increased CRT (zone 1) and RNFL thickness compared to the controls and no-ME-RP (p ≤ 0.002). The no-ME-RP group had reduced CRT thickness (all zones; p ≤ 0.018) compared to the controls and ME-RP, whereas the RNFL thickness in the no-ME-RP group was reduced only compared to the ME-RP group (p < 0.001). The ME-RP group showed significantly more attenuated functional responses than the no-ME-RP patients. A significant positive interaction was found between the CRT (zones 1 and 2) and the RNFL thickness within ME-RP (p ≤ 0.010). Significant negative interactions were found between CRT, RNFL thickness, and functional findings within ME-RP (p ≤ 0.049). Conclusion The presence of macular oedema correlated well with increased RNFL thickness and residual function in RP patients. Such association provides evidence of an underlying transneuronal mechanism of retinal degeneration. Simultaneous monitoring of CRT and RNFL thickness may help in the future to evaluate the progression of the disease and the efficacy of treatments in RP patients.

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“…Within the field of gene therapy, AAV vectors have been used extensively for therapeutic transgene delivery and in clinical trials for retinal disease they have shown good safety with minimal adverse events [59]. In the case of STGD1 treatments, early attempts involved creation of a single "oversized" transgene containing the complete 6.8 kb ABCA4 coding sequence.…”

Section: Adeno-associated Viral Vectorsmentioning

confidence: 99%

Therapy Approaches for Stargardt Disease

2021

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Despite being the most prevalent cause of inherited blindness in children, Stargardt disease is yet to achieve the same clinical trial success as has been achieved for other inherited retinal diseases. With an early age of onset and continual progression of disease over the life course of an individual, Stargardt disease appears to lend itself to therapeutic intervention. However, the aetiology provides issues not encountered with the likes of choroideremia and X-linked retinitis pigmentosa and this has led to a spectrum of treatment strategies that approach the problem from different aspects. These include therapeutics ranging from small molecules and anti-sense oligonucleotides to viral gene supplementation and cell replacement. The advancing development of CRISPR-based molecular tools is also likely to contribute to future therapies by way of genome editing. In this we review, we consider the most recent pre-clinical and clinical trial data relating to the different strategies being applied to the problem of generating a treatment for the large cohort of Stargardt disease patients worldwide.

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Treatment-Emergent Adverse Events in Gene Therapy Trials for Inherited Retinal Diseases: A Narrative Review

Cited by 22 publications

References 122 publications

Optogenetic Gene Therapy for the Degenerate Retina: Recent Advances

Optogenetic Gene Therapy for the Degenerate Retina: Recent Advances

Linking the Presence of Macular Oedema to Structural and Functional Alterations in Retinitis Pigmentosa

Therapy Approaches for Stargardt Disease

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