Ocular Inflammation and Treatment Emergent Adverse Events in Retinal Gene Therapy

Mehta, Neesurg; Robbins, Deborah A; Yiu, Glenn

doi:10.1097/iio.0000000000000366

Cited by 19 publications

(8 citation statements)

References 120 publications

(281 reference statements)

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“…Various factors affect the severity of the immune response, such as viral vectors used, administration route, and viral dose, including several others [37].…”

Section: Immune Responementioning

confidence: 99%

“…However, the immunogenicity of viral vectors, their capsids, the transgene, and the transgene product as a foreign body can activate immune responses. Various factors affect the severity of the immune response, such as viral vectors used, administration route, and viral dose, including several others [ 37 ].…”

Section: Reviewmentioning

confidence: 99%

“…However, cross-reactivity between serotypes is possible. AAVs only generate favourable immune responses, hence they are the preferred vector for ocular gene therapy [ 37 ].…”

Section: Reviewmentioning

confidence: 99%

“…This is because the viral particles from the vitreous, through Schlemm’s canal and reach the systemic circulation and lymphatic flow and can activate an immune response. The subretinal space is relatively immune-privileged and shows a very mild immune response [ 37 ].…”

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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“…Various factors affect the severity of the immune response, such as viral vectors used, administration route, and viral dose, including several others [37].…”

Section: Immune Responementioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

“…However, cross-reactivity between serotypes is possible. AAVs only generate favourable immune responses, hence they are the preferred vector for ocular gene therapy [ 37 ].…”

Section: Reviewmentioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

See 2 more Smart Citations

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

Wasnik¹,

Thool²

2022

Cureus

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show abstract

“…Yet, diffusion through the optic nerves to the other eye and to the brain cannot be excluded and has been advocated as a potential explanation for the bilateral effects of lenadogene nolparvovec, an AAV-2 serotype 2, containing a codon-optimized complementary DNA encoding the human wildtype MT-ND4 subunit protein, injected into the vitreous of one eye of patients with Leber hereditary optic neuropathy, resulting in a clinical effect in the contralateral, noninjected eye [ 93 ]. It is not fully understood how, but clinical studies have shown that intravitreous injection of viral vectors can elicit an inflammatory and immune response with potential deleterious consequences, which has reduced the enthusiasm for intravitreous viral vector delivery [ 94 , 95 ]. Gene delivery and oligonucleotide delivery to retinal cells remains a challenge.…”

Section: Description Of Ocular Barriersmentioning

confidence: 99%

Ocular Barriers and Their Influence on Gene Therapy Products Delivery

2022

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The eye is formed by tissues and cavities that contain liquids whose compositions are highly regulated to ensure their optical properties and their immune and metabolic functions. The integrity of the ocular barriers, composed of different elements that work in a coordinated fashion, is essential to maintain the ocular homeostasis. Specialized junctions between the cells of different tissues have specific features which guarantee sealing properties and selectively control the passage of drugs from the circulation or the outside into the tissues and within the different ocular compartments. Tissues structure also constitute selective obstacles and pathways for various molecules. Specific transporters control the passage of water, ions, and macromolecules, whilst efflux pumps reject and eliminate toxins, metabolites, or drugs. Ocular barriers, thus, limit the bioavailability of gene therapy products in ocular tissues and cells depending on the route chosen for their administration. On the other hand, ocular barriers allow a real local treatment, with limited systemic side-effects. Understanding the different barriers that limit the accessibility of different types of gene therapy products to the different target cells is a prerequisite for the development of efficient gene delivery systems. This review summarizes actual knowledge on the different ocular barriers that limit the penetration and distribution of gene therapy products using different routes of administration, and it provides a general overview of various methods used to bypass the ocular barriers.

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