Expert highlights current potentials, limitations of gene therapy for corneal disease
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Gene therapy for corneal disease holds promise but still has limitations, according to one speaker at the virtual EuCornea congress.
“In ophthalmology, most clinical trials are related to disorders of the retina, while for cornea, they are still very few,” Victor Abad Morales, PhD, said.
He said that requirements for corneal gene therapy are stringent. First, vision must be significantly impaired or likely to be so in the near future, and no better equivalent effective treatment must be available. Second, the genetic defect involved must be clearly identified, and third, the delivery of the genetic material must be practical and safe, leading to durable modulation of the corneal pathology.
“If we have identified the genetic cause of the disease, we must further understand the underlying molecular pathology, meaning the mutation effect of the genetic alteration, the so-called genotype that leads to a certain corneal disease or phenotype,” Abad Morales said.
Depending on the mutation, there can be different alterations, classified as loss of function, dominant negative effect or haploinsufficiency. Identifying the type of effect is crucial to determine the therapeutic strategy.
Gene therapy consists of three possible strategies: gene augmentation, gene silencing and gene editing. Recently, the CRISPR/Cas9 gene editing technique has shown clinical potential to correct genetic alterations and restore normal function.
“CRISPR/Cas9 presents many advantages, including the simple design of the target, with higher efficacy and ability to induce mutations in multiple genes at the same time. However, the generation of off-target effects, targeting efficiency and the necessity of an individualized design for each mutation are still major limitations,” Abad Morales said.
As far as delivery systems are concerned, viral and non-viral vectors have different advantages and limitations.
“Most viral vectors present important limitations concerning safety and immunogenicity. Moreover, adenoviruses and retroviruses are of limited use for corneal gene therapy due to their inability to transduce low or non-dividing cells such as corneal endothelium and keratocytes. On the other hand, non-viral vectors, such as lipids and nanoparticles, are generally safe but less efficient,” Abad Morales said.
Adeno-associated viruses seem the most promising delivery system, he said, “although they present a major disadvantage: a low packaging capacity that limits gene therapy for large genes.”
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Abad Morales V. Limitations of gene therapy application. Presented at: EuCornea congress; Sept. 26, 2020 (virtual meeting).
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