Efficacy and Safety of Glycosidic Enzymes for Improved Gene Delivery to the Retina following Intravitreal Injection in Mice

Cehajic-Kapetanovic, Jasmina; Milosavljevic, Nina; Bedford, Robert A.; Lucas, Robert J.; Bishop, Paul

doi:10.1016/j.omtm.2017.12.002

Cited by 23 publications

(18 citation statements)

References 44 publications

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“…Transduction of the innermost layer of the retina, the retinal ganglion cells has been readily achieved in mouse models following intravitreal injection ( Yin et al, 2011 ; Smith and Chauhan, 2018 ). Wild type AAV capsid transduction appears limited to the retinal ganglion cells unless applying an additional adjunctive ( Cehajic-Kapetanovic et al, 2011 , 2018 ) whereas modified AAV capsids penetrate further following intravitreal injection into the inner retina ( Kay et al, 2013 ; Hickey et al, 2017 ; van Wyk et al, 2017 ).…”

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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“…Interestingly, retinal AAV2 transduction was increased by co-injection of glycosaminoglycan-degrading enzymes. Adopting the same approach, we co-injected pronase E, a mixture of peptidases hydrolyzing glycoproteins, or a combination of heparinase III and hyaluronan lyase, with the α-syn PFFs ( Dalkara et al, 2009 ; Cehajic-Kapetanovic et al, 2018 ). Nevertheless, although the effectivity of the enzymatic digestions was confirmed with a laminin staining ( Figures 3A–C ), as previously described in Dalkara et al (2009) , these treatments did not promote α-syn PFF infiltration in the retina ( Figures 3A,B ).…”

Section: Resultsmentioning

confidence: 99%

Absence of Uptake and Prion-Like Spreading of Alpha-Synuclein and Tau After Intravitreal Injection of Preformed Fibrils

Veys

houcke

Aerts

et al. 2021

Front. Aging Neurosci.

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Although very different in etiology and symptoms, numerous neurodegenerative diseases can be classified as proteinopathies. More so, evidence indicates that the key misfolded proteins at the basis of different neuropathies might share common mechanisms of propagation. As such, the prion-like spreading of protein aggregates through the neural network is subject of intensive research focus and requires adequate models. Here, we made use of the well-defined architecture and large accessibility of the visual system, of which the retinotopic connections represent a simple route of anterograde signaling and an elegant model to investigate transsynaptic, prion-like spreading. In two independent studies, uptake and seeding of alpha-synuclein and tau were examined after intravitreal injection of preformed fibrils. However, extracellular matrix components in the vitreous space and at the vitreoretinal surface appeared to act as a barrier for the entry of both fibrils into the retina. These results show that further experimental refinement is needed to fully realize the potential of the visual system as a model for studying the molecular and cellular mechanisms of anterograde, transsynaptic spreading of prion-like proteins.

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“…Intravitreal injections of empty rAAV capsids can induce a temporary immune inflammation of the aqueous and the vitreous [ 303 ]. Enzymatic digestion (proteasome inhibitors) of the ILM or ILM/outer limiting membrane (OLM) or disruptions of the ILM/OLM by the disease can alter rAAV infection and allow rAAV infection deeper into the retina [ 99 , 294 , 304 , 305 ]. Applying a low trans-ocular electric current also allowed efficient transduction of RPE and photoreceptors by rAAV8 upon intravitreal injection in adult mice [ 306 ].…”

Section: Transgene and Bioactivity Assays In Ocular Tissuementioning

confidence: 99%

Recombinant Adeno-Associated Viral Vectors (rAAV)-Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays

Buck

Wijnholds

2020

IJMS

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Inherited retinal dystrophies and optic neuropathies cause chronic disabling loss of visual function. The development of recombinant adeno-associated viral vectors (rAAV) gene therapies in all disease fields have been promising, but the translation to the clinic has been slow. The safety and efficacy profiles of rAAV are linked to the dose of applied vectors. DNA changes in the rAAV gene cassette affect potency, the expression pattern (cell-specificity), and the production yield. Here, we present a library of rAAV vectors and elements that provide a workflow to design novel vectors. We first performed a meta-analysis on recombinant rAAV elements in clinical trials (2007–2020) for ocular gene therapies. We analyzed 33 unique rAAV gene cassettes used in 57 ocular clinical trials. The rAAV gene therapy vectors used six unique capsid variants, 16 different promoters, and six unique polyadenylation sequences. Further, we compiled a list of promoters, enhancers, and other sequences used in current rAAV gene cassettes in preclinical studies. Then, we give an update on pro-viral plasmid backbones used to produce the gene therapy vectors, inverted terminal repeats, production yield, and rAAV safety considerations. Finally, we assess rAAV transgene and bioactivity assays applied to cells or organoids in vitro, explants ex vivo, and clinical studies.

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Efficacy and Safety of Glycosidic Enzymes for Improved Gene Delivery to the Retina following Intravitreal Injection in Mice

Cited by 23 publications

References 44 publications

Optogenetic Gene Therapy for the Degenerate Retina: Recent Advances

Optogenetic Gene Therapy for the Degenerate Retina: Recent Advances

Absence of Uptake and Prion-Like Spreading of Alpha-Synuclein and Tau After Intravitreal Injection of Preformed Fibrils

Recombinant Adeno-Associated Viral Vectors (rAAV)-Vector Elements in Ocular Gene Therapy Clinical Trials and Transgene Expression and Bioactivity Assays

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