This story is part of a series on the current progression in Regenerative Medicine. This piece is part of a series dedicated to the eye and improvements in restoring vision. 

In 1999, I defined regenerative medicine as the collection of interventions that restore to normal function tissues and organs that have been damaged by disease, injured by trauma, or worn by time. I include a full spectrum of chemical, gene, and protein-based medicines, cell-based therapies, and biomechanical interventions that achieve that goal.

Gene therapy can potentially address a wide range of acute and chronic diseases. The application of gene therapy to restoring vision has been especially fruitful. Here we discuss the potential of gene therapy to address macular degeneration. According to the World Health Organization (WHO), age-related macular degeneration affects over 196 million people globally. The incidence of the disease will likely increase in the coming years as a consequence of aging populations in many countries.

These findings have prompted researchers to develop intervention strategies based on individual polygenic risk scores. However, interpreting these scores at a personal level may be challenging. As a result, more traditional approaches to gene therapy and gene editing have been considered for age-related macular degeneration.


Gene Therapy & Gene Editing: Two Effective Tools for Addressing Deleterious Genes

Gene therapy and gene editing are two different approaches to treating genetic mutations. Gene therapy replaces a defective gene with a functional one through a delivery vector. Gene editing, on the other hand, involves manipulating the target gene at the DNA or genomic level. CRISPR-based gene technologies permit both substitution of entire genes and the editing of small region target sequences. CRISPR-based treatments have been studied for retinal disorders such as retinitis pigmentosa

Over the past five decades, gene therapy has evolved from a simple concept to the subject of over 1400 clinical trials across the globe, offering a degree of innovation and intervention never seen before. More particularly, viral vector gene therapy has emerged as an innovative treatment option for retinal diseases such as wet and dry age-related macular degeneration, paving the way for revolutionary treatment plans that could significantly improve patient outcomes.


What Are Vectors For Gene Therapy?

In gene therapy, a vector is a vehicle that delivers therapeutic genes or nucleic acids to target cells to treat genetic disorders or diseases. Typically, vectors can be divided into two categories, viral and nonviral vectors. Viral vectors utilize modified viruses to deliver the desired gene to the target cells. In contrast, nonviral vectors use alternative methods to provide genes to target cells. 

Messenger RNA (mRNA) has emerged as a nonviral gene therapy vector that shows promising potential in inducing cellular and therapeutic immune responses. Through its versatile protein delivery mechanism and dendritic cells’ potent antigen-presenting abilities, mRNA can deliver genetic information to treat various inherited and acquired diseases. mRNA is also often used alongside CRISPR for retinal disorders, cancer treatment, and other CAR T therapies.

The inability to integrate into the host genome and the strictly transient expression are additional benefits that make mRNA therapy a promising avenue for safe and effective gene therapy. However, viral vectors often have greater efficiency in transferring genes to target cells than nonviral vectors, and researchers have therefore been working on modifying viral vectors to reduce the risks involved in their use in human subjects. 

The concept of using viruses as vectors dates back to the 1970s. However, it wasn’t until the 1980s that scientists could manipulate viral genomes without adverse effects. Recently, the spotlight has fallen on adeno-associated viral, or AAV, vectors. AAVs are a class of small DNA viruses that infect humans and other primates without causing illness. These developments have enabled new applications in gene therapy, with their use surging in clinical trials.

Scientific research has discovered that in mouse muscle tissue, in vivo administration of AAV vectors can provide long-term transgene expression and effective relief. By requiring a helper virus to replicate, AAV vectors present a significant advantage because they are unlikely to be associated with a disease. Thus, essential proteins coding for viral replication and integration can be removed from the AAV genome.

Moreover, AAV vectors have demonstrated a capacity to elicit a relatively mild immune response, mitigating the chance of producing a host immune response while substantially decreasing the overall vector dose required for therapeutic efficacy. This lessened risk inherent in AAV vector therapeutics makes them particularly promising for clinical trial exploration.


A Landmark for Retinal Gene Therapy

The suitability of eyes as targets for gene therapy stems from the fact that individual genes are responsible for different conditions, making it possible to replace a single gene to minimize payload delivery for AAV vectors and avoid potential errors arising from large transgenes. Furthermore, the potential of a single gene therapy dose presents a marked improvement over frequent intravitreal injections to treat retinal diseases. 

One of the landmark breakthroughs in gene therapy occurred when three clinical trials evaluated the efficacy of adeno-associated virus serotype 2 vectors carrying a functional copy of the retinal pigment epithelium-specific 65-kDa protein gene, or RPE65. This gene encodes the RPE65 protein, critical in the biological conversion of light photons into electrical signals transmitted to the brain via the optic nerve.

This groundbreaking research led to the FDA’s approval of the first-ever ocular gene therapy: Voretigene Neparvovec-rzyl, also called Luxturna. Spark Therapeutics develops Luxturna to treat confirmed cases of inherited retinal dystrophy caused by RPE65 mutations. Approved by the United States Food & Drug Administration in December 2017, Luxturna is a one-time subretinal injection of a functional copy of the RPE65 gene that becomes transduced into the retinal cells. 

The injection of Luxturna delivers a functional copy of the RPE65 gene to the retinal cells, allowing the production of RPE65-specific protein, which is crucial for the retinoid cycle. By restoring the retinoid process, Luxturna aims to improve vision and preserve existing vision. Today, Luxturna is being administered at ten treatment centers in the United States, and it remains a significant breakthrough in gene therapy.

Since the approval of Luxturna, other clinical trials evaluating gene therapies have reported positive results, indicating that gene therapy could revolutionize age-related macular degeneration treatment plans.

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