Gene therapy is mainly an experimental treatment utilising genes to treat or halt the progression of inherited conditions. In ophthalmology, it is primarily researched in inherited retinal dystrophies (IRDs), a group of conditions caused by any one of more than 250 types of genetic mutations that leads to gradual degeneration of photoreceptor cells in the retina, resulting in visual loss.
Some of the genetic mutations associated with IRDs lead to insufficient or absence in production of a specific protein (loss-of-function mutations), which eventually causes cell death. With gene therapy, the mutated gene in the affected retinal cells is replaced with a normal healthy copy of the gene. This enables the cells to regain some of its function and produce the required protein for survival, thereby restoring parts of vision or preserving remaining sight.
Apart from replacing genes affected by loss-of-function mutations, other mechanisms of gene therapy include inactivating a mutated gene that is not working properly and introducing a gene to fight a specific disease.
The rest of this section mainly focuses on gene therapy for loss-of-function mutations as the latter two mechanisms are not widely researched in ophthalmology currently.
How does it work?
A vector is required to “transport” the normal healthy gene copy and introduce it to the affected cells. Viruses are commonly used vectors in gene therapies due to their ability to penetrate into the cells. One of the most commonly used vectors in ophthalmology is the adeno-associated virus (AAV). Lentivirus is another type of virus under research for similar purposes.
The viral vectors are bioengineered initially to prevent them from causing illness prior to introduction to human cells. The normal gene copy is then “packaged” into the vectors and then injected into the retina either through surgery (subretinal injection) or through a common outpatient procedure called intravitreal injection. The type of procedure depends on the location of the affected cells.
Gene therapy in clinical practice
Although still primarily an experimental treatment, voretigene neparvovec (Luxturna®) became the first gene therapy licensed for clinical use in ophthalmology by the US Food and Drug Administration (FDA) in December 2017. This was later followed by the UK’s National Institute for Health and Care Excellence (NICE) in September 2019.
Luxturna® is an AAV based gene therapy licensed for the treatment of IRDs associated with mutations in the RPE65 gene. It provides instructions for retinal cells to produce the RPE65 enzyme, a key component in a multistep process called the visual cycle. The visual cycle converts light entering the eye into electrical signals to generate vision.This involves the recycling of visual pigments by the RPE65 enzyme (and other enzymes) in the retinal cells. Deficiency of this key enzyme disrupts the visual cycle and consequently leads to vision loss.
One of the main symptoms of RPE65 related IRD is difficulty seeing at night from birth. The pivotal trial (Russell and colleagues 2017) leading to the FDA’s approval of Luxturna showed patients who received treatment to both eyes (sequentially at different periods) have improved navigational abilities at low light levels compared to those that did not receive treatment. This finding reflected the improved visual function observed in patients receiving Luxturna in an earlier trial (Maguire and colleagues 2009). The improvement was sustained over at least three years with observations still ongoing (Bennett and colleagues 2016).
Patients with RPE65 gene mutations are not the only ones that might benefit from gene therapy. Although Luxturna® is currently the only licensed therapy, there are various gene therapy trials at the phase 1 or phase 2 stages being conducted for IRDs caused by other genetic mutations.
Conditions with gene therapy clinical trials
- Leber congenital amaurosis 2 (LCA2)
- Leber hereditary optic neuropathy (LHON)
- Retinitis pigmentosa
- X-linked juvenile retinoschisis
1) Limited carrying capacity of AAV
AAV has a cargo capacity of approximately 5 kilobases (kb—a unit measure for the length of a DNA chain). Many IRDs are caused by mutations in much larger genes, such as the ABCA4 gene (just over 7kb) associated with Stargardt disease and the MYO7A gene (87kb) associated with Type 1B Usher Syndrome (USH1B).
To overcome this, researchers tried splitting these larger genes into two parts, which will then recombine when the AAV vectors carrying these fragments are injected into the affected retinal cells (dual AAV therapy). This method was successful in treating the mice models of Stargardt’s disease and USH1B. As a result, there are ongoing plans for a phase 1/2 clinical trial on dual AAV gene therapy for USH1B funded by the European Commission’s Community Research and Development Information Service (CORDIS).
Lentivirus, with a cargo capacity of 10-11kb, is another alternative. However, unlike AAV, lentiviruses have the ability to insert their DNA into the host’s own DNA sequence, potentially causing harmful genetic mutations.
2) Risk of immune reaction to the viral vector
Although AAV is not associated with any known human diseases, it is considered a foreign protein by our body and therefore it will mount an immune response, like fighting an infection. Therefore, patients receiving gene therapy at present are required to take steroid tablets few days before and after surgery to modulate this response.
In addition, it is not known how the body’s immune system will respond to the same AAV vector that has been previously introduced. As a result, gene therapies such as Luxturna® is currently a “one-and-done” treatment, meaning if the first dose of viral vector-mediated gene therapy is ineffective, patients are not allowed to get a second dose.
3) High cost
Companies developing gene therapies have spent huge amount of money on research and development, a cost that needs to be recouped. As inherited eye disorders are relatively rare, the development costs are therefore spread over smaller number of patients. For example, the list price of Luxturna for the National Institute for Health and Care Excellence (NICE) is £613,410 per patient. Fortunately, a commercial arrangement between NHS England and the company producing it has driven the cost down, making it available to NHS patients.
Related experimental treatments
- Daiger SP. RetNet: Summaries of Genes and Loci Causing Retinal Diseases. https://sph.uth.edu/retnet/sum-dis.htm#B-diseases. Published 2019. Updated 29 October 2019. Accessed 9 November 2019.
- Trapani I, Auricchio A. Seeing the Light after 25 Years of Retinal Gene Therapy. Trends Mol Med. 2018;24(8):669-681.
- Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390(10097):849-860
- Maguire AM, High KA, Auricchio A, et al. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet. 2009;374(9701):1597-1605.
- Bennett J, Wellman J, Marshall KA, et al. Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial. Lancet. 2016;388(10045):661-672.
- Trapani I, Colella P, Sommella A, et al. Effective delivery of large genes to the retina by dual AAV vectors. EMBO Mol Med. 2014;6(2):194-211.
- Cavalieri V, Baiamonte E, Lo Iacono M. Non-Primate Lentiviral Vectors and Their Applications in Gene Therapy for Ocular Disorders. Viruses. 2018;10(6).
- Ramlogan-Steel CA, Murali A, Andrzejewski S, Dhungel B, Steel JC, Layton CJ. Gene therapy and the adeno-associated virus in the treatment of genetic and acquired ophthalmic diseases in humans: Trials, future directions and safety considerations. Clin Exp Ophthalmol. 2019;47(4):521-536.
- National Institute for Health and Care Excellence (NICE). NICE recommends novel gene therapy treatment for rare inherited eye disorder. https://www.nice.org.uk/news/article/nice-recommends-novel-gene-therapy-treatment-for-rare-inherited-eye-disorder. Published 2019. Updated 4 September 2019. Accessed 9 November 2019.