Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses

Ghoraba, Hashem; Akhavanrezayat, Amir; Karaca, Irmak; Yavari, Negin; Lajevardi, Sherin; Hwang, Jaclyn Joyce; Regenold, Jonathan; Matsumiya, Wataru; Pham, Brandon; Zaidi, Moosa; Mobasserian, Azadeh; DongChau, Anthony Toan; Or, Christopher; Yaşar, Çigdem; Mishra, Kapil; Do, Diana; Nguyen, Quan Dong

doi:10.2147/opth.s364200

Cited by 33 publications

(31 citation statements)

References 98 publications

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“…The eye has long been considered as an immune-privileged organ, in which immune responses are often deviated toward protolerogenic responses. However, inflammatory immune responses can nevertheless occur, as seen in pathologies such as uveitis and also as shown by our own data [40][41][42] .…”

Section: Discussionsupporting

confidence: 76%

Cellular Immune Responses Induced by Subretinal AAV Gene Transfer can be Restrained by the Subretinal Associated Immune Inhibition Mechanism

Vendomèle

CHAUVEAU

Dalkara

et al. 2023

Preprint

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For more than a decade, AAV-mediated gene transfer has been tested successfully in clinical trials to treat inherited retinal diseases. Despite the eye's immune-privileged status and the use of corticoids as an adjunct treatment, some patients display inflammatory events which led us to question the immune consequences of a subretinal AAV administration. We first characterized anti-transgene immune responses induced in the periphery by injecting increasing doses of AAV8 encoding reporter proteins fused with the HY male antigen into the subretinal space of female C57BL/6 and rd10 mice. Transgene expression was monitored over time with bioluminescence imaging and T-cell immune responses in the spleen were analyzed by IFNγ ELISpot and cytokine multiplex assays. Our data show that an AAV8 injection causes proinflammatory T-cell immune response against the transgene product, correlated with the transgene expression level at 2.109 vg and above. Additionally, co-injection of immunodominant peptides from the transgene product, along with AAV8, modulates the immune response at all AAV doses tested. Taken together, our data suggest that injection of AAV8 in the subretinal space induces proinflammatory peripheral T-cell responses to the transgene product that can be modulated by the subretinal associated immune inhibition (SRAII) mechanism.

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Section: Discussionsupporting

confidence: 76%

Cellular Immune Responses Induced by Subretinal AAV Gene Transfer can be Restrained by the Subretinal Associated Immune Inhibition Mechanism

Vendomèle

CHAUVEAU

Dalkara

et al. 2023

Preprint

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“…LNPs, nano polymers, and self-assembly peptides with nucleic acid are the most common non-viral delivery systems in this area. There are several studies and clinical trials on ocular gene therapy for immunomodulatory approaches using siRNA, miRNA, mRNA, DNA, and plasmid DNA (Ghoraba et al, 2022).…”

Section: Nucleic Acidsmentioning

confidence: 99%

Roles of biomaterials in modulating the innate immune response in ocular therapy

Rafiei

Chung²,

Chau³

2023

Front. Drug Deliv.

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The eye is a hard-to-treat organ due to its poor regenerative capacity and susceptibility to inflammation; as a result, it has an immune privilege mechanism. In the case of ocular degenerative disorders, chronic and uncontrolled ocular inflammations can overcome this immune response to initiate and exacerbate tissue degeneration, ultimately leading to blindness. Recent landmark discoveries on the key roles of the ocular innate immune system in regulating acute and chronic inflammations as well as tissue fibrosis and homeostasis have shed light on the value of novel treatment interventions in modulating ocular immune responses at the molecular, cellular, and tissue levels. This strategy can be attained by using therapeutics to target resident phagocytes and antigen-presenting cells, namely, microglia and dendritic cells, as well as infiltrating neutrophils and macrophages. Biomaterials are foreign materials to the host and interact with innate immune cells. To leverage such intrinsic immunomodulatory properties, biomaterials such as implants, injectable depots, and nano/micro particles can be used alone as a treatment or with different payloads as carriers in immune-related ocular disorders. This article discusses how physicochemical properties such as biodegradability, size, shape, and charge affect biomaterials’ interaction with the eye’s innate immune system, therefore influencing outcomes towards pro- or anti-inflammatory responses. Knowledge about the eye’s immunological response is required for designing tolerogenic biomaterials including intraocular lenses, cellular scaffolds, therapeutic molecule depots, or carriers of gene therapies. The discussion presented in this review will shed light on the potential use of biomaterials to direct immune responses toward favorable treatment outcomes.

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“…Chromophore forms visual pigments in photoreceptors of the retina. This leads to visual impairment [ 18 ].…”

Section: Reviewmentioning

confidence: 99%

“…Autosomal recessive is the most common. More than 70 genes are found to be concerned with the development of retinitis pigmentosa [ 18 ].…”

Section: Reviewmentioning

confidence: 99%

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Ocular Gene Therapy: A Literature Review With Focus on Current Clinical Trials

Wasnik¹,

Thool²

2022

Cureus

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Gene therapy has been one of the most researched topics in the last decade. It has now become a revolutionized therapeutic tool of modern medicine. Gene therapy is the alteration of the defective gene involved in the disease process in the host cells. It delivers therapeutic genetic information via modified viral or non-viral vectors. Ocular gene therapy, in particular, has progressed in treating inherited retinal diseases since the eye is a favourable organ for gene therapy development. The advantage of the eye as a target for gene therapy is attributed to its easy accessibility and blood-ocular barrier. Several ongoing clinical trials are investigating various gene therapies for other ocular diseases, including neovascular agerelated macular degeneration, retinitis pigmentosa (RP), Usher syndrome, glaucoma, and several others. However, there are challenges such as ocular inflammation and humoral response, infection by the viral vectors, and insertional mutagenesis. These limitations depend on several factors; whether viral or non-viral vectors are used, which viral vectors were used, the route of administration, whether subretinal, intravitreal, or suprachoroidal, and the dose of vectors and the target tissue. These complications may lead to therapeutic failure and vision loss due to intraocular inflammation. This review aims to summarize existing knowledge about ocular gene therapy and the associated limitations we face, with a special focus on a few ongoing clinical trials.

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Ocular Gene Therapy: A Literature Review with Special Focus on Immune and Inflammatory Responses

Cited by 33 publications

References 98 publications

Cellular Immune Responses Induced by Subretinal AAV Gene Transfer can be Restrained by the Subretinal Associated Immune Inhibition Mechanism

Cellular Immune Responses Induced by Subretinal AAV Gene Transfer can be Restrained by the Subretinal Associated Immune Inhibition Mechanism

Roles of biomaterials in modulating the innate immune response in ocular therapy

Ocular Gene Therapy: A Literature Review With Focus on Current Clinical Trials

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