Gene therapy


Gene therapy utilises genes to treat or halt the progression of hereditary conditions, primarily in inherited retinal dystrophies (IRD). IRD comprises of multiple conditions caused by mutations in any one of more than 300 genes[1] that eventually leads to gradual degeneration of photoreceptor cells in the retina and subsequent visual loss.

Most of these gene mutations lead to missing or defective protein production, causing the retinal cells not to function properly. With gene therapy, the mutated gene is replaced with a normal healthy copy of the gene. This enables the retinal cells to regain some of its function and produce the required protein for survival, thereby restoring parts of vision or preserving remaining sight.

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How does it work?

The normal gene copy is packaged into a harmless virus. The virus then breaches the target cells and delivers the normal gene copy to the cell's DNA mechanism. As a result, the cell is now making normal and functional protein.
Principles of gene therapy

A normal healthy gene copy is first “packaged” into a vehicle (or medically known as a vector) to transport it to the affected retinal cells. Viruses are commonly used vectors due to their ability to penetrate into cells and effectively integrate the genetic materials they are carrying. Adeno-associated virus (AAV) and lentivirus are the preferred vectors for IRD related gene therapies. The viruses are rendered harmless initially before introduction to human cells.

Once the viruses are packaged with the intended replacement genes, they are injected into the retina either through surgery (sub-retinal injection) or through a common outpatient procedure called intravitreal injection. The type of injection depends on the location of the affected cells.

Sub-retinal injection is the primary method used currently to administer gene therapy as most IRDs are due to dysfunctional photoreceptors or their supporting cells, called the retinal pigment epithelium (RPE) which are located deep in the retina. With this technique, the viral vectors are able to reach their target cells more easily, giving the treatment a higher chance of success. Intravitreal injections are mainly for conditions where the affected cells are more superficial or when the retina is at high risk of retinal detachment.

The normal gene copy is packaged into a harmless virus, which is then injected below the retina through surgery. This allows maximum exposure of the photoreceptors to the injected therapy.
Sub-retinal injection of gene therapy
An injection into the clear jelly of the eye called the vitreous. This is a commonly performed outpatient procedure by eye doctors around the world for other conditions.
Intravitreal injection

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Is it available to patients now?

Luxturna (voretigene neparvovec) was approved for clinical use by the US Food and Drug Administration (FDA) in December 2017.[2] The UK’s National Institute for Health and Care Excellence (NICE) followed suit in September 2019, making it available to all NHS patients.[3]

Luxturna is an AAV based gene therapy for the treatment of IRD caused by mutations in the RPE65 gene. One of the main symptoms of RPE65 related IRD is difficulty seeing at night from birth. The pivotal trial[4] reported by Russell and colleagues in 2017 showed patients who received treatment to both eyes (sequentially at different periods) have improved visual function and navigational abilities at low light levels compared to those that did not receive treatment. The improvement has been sustained up to 4 years after the initial surgery.

There are four treatment centres in the UK currently offering this treatment:

Patients with RPE65 gene mutations are not the only ones that might benefit from gene therapy. Although Luxturna is currently the only approved therapy, there are various gene therapy trials at earlier stages (phase 1 or phase 2) being conducted for IRDs caused by other gene mutations.

Related links

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Conditions with gene therapy trials

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Is it safe?

Based on trial results available so far, AAV mediated gene therapy in the eye is considered safe. The most commonly reported side effects were limited to the injected eye and related to the injection procedure itself. These included mild and transient eye inflammation, transiently elevated eye pressure and retinal tears, all of which resolved either with eye drops or laser treatment. Serial blood tests showed minimal immune response from the body.

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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 1 Usher Syndrome (USH1).[5]

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 retinal (dual AAV therapy). This method was successful in treating the mice models of Stargardt disease and USH1.[6] As a result, there are ongoing plans for a phase 1/2 clinical trial on dual AAV gene therapy for USH1 funded by the European Commission’s Community Research and Development Information Service (CORDIS).

Lentivirus, with a cargo capacity of 10-11kb, is another alternative.[7] However, unlike AAV, lentiviruses have the ability to insert their DNA into the host’s own DNA sequence, potentially causing harmful genetic mutations.[8] Phase 1/2 trials on lentiviral gene therapy (SAR 422459) for USH1 (NCT 01505062) and Stargardt disease (NCT 01367444) were conducted. Only 9 participants were recruited to the USH1 trial before the trial sponsor decided to stop developing the treatment prematurely. The 1-year result for the Stargardt disease trial showed that SAR 422459 was safe and well-tolerated with no clear evidence of visual improvement but it has met the same fate as the USH1 trial. Only a long-term follow-up study (NCT 01736592) of the treated Stargardt patients is being conducted at present.

2) Risk of immune reaction to the viral vector

Although AAV is not associated with any known human diseases,[9] 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 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 into the same eye.[8] As a result, gene therapies such as Luxturna is currently a “one-and-done” treatment, meaning if the first dose is ineffective, patients are not allowed to get a second dose in the same eye.

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.[3] However, a commercial arrangement between NHS England and the company producing it has driven the cost down, making it available to NHS patients.

4) Unknown long term side effects and therapeutic effect

Although AAV mediated gene therapy seems to be safe whilst sustaining its treatment effect in the short term, its long term outlook is unknown with the longest follow-up being only 4 years. [9-11] Hence, many gene therapy trials are continuing to observe participants for a longer period of time.

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Looking forward

Given some of the limitations associated with viral gene therapy, an alternative approach that is currently being developed to overcome these issues is a non-viral gene delivery system, containing a human DNA element called scaffold/matrix attachment regions (S/MAR) to encase the normal copy of the gene of interest. S/MAR vectors have several benefits:

  • Capacity to hold large genes 
  • Do not integrate into the patient’s DNA, thus reducing the risk of introducing cancer-related mutations 
  • Do not have any viral components and therefore reducing any response from our own body’s immune system 
  • Long-term gene expression (as long as 2 years has been noted in animal models)

Together this suggests that S/MAR vectors are safe and effective for gene delivery, and research is underway to assess this using stem cell and zebrafish models of Usher syndrome. Non-viral S/MAR vectors may revolutionise the treatment of inherited retinal dystrophies by providing a safer and more applicable form of gene therapy in the future.

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  1.  Daiger SP. RetNet: Summaries of Genes and Loci Causing Retinal Diseases. Published 2019. Updated 29 October 2019. Accessed 9 November 2019.
  2.  U.S. Food and Drug Administration (FDA). FDA approves novel gene therapy to treat patients with a rare form of inherited vision loss. Published 2017. Updated 16 March 2018. Accessed 12 February 2020.
  3.  National Institute for Health and Care Excellence (NICE). NICE recommends novel gene therapy treatment for rare inherited eye disorder. Published 2019. Updated 4 September 2019. Accessed 9 November 2019.
  4.  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.
  5.  Trapani I, Auricchio A. Seeing the Light after 25 Years of Retinal Gene Therapy. Trends Mol Med. 2018;24(8):669-681.
  6.  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.
  7.  Cavalieri V, Baiamonte E, Lo Iacono M. Non-Primate Lentiviral Vectors and Their Applications in Gene Therapy for Ocular Disorders. Viruses. 2018;10(6).
  8.  Moosajee M. A No-Nonsense Approach to Inherited Disease. The Ophthalmologist Web site. Published 2019. Updated 7 August 2019. Accessed 9 November 2019.
  9.  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.
  10.  Healio Ocular Surgery News. Improvements maintained at 4 years after Luxturna administration. Accessed 18 December 2019,
  11.  GenSight Biologics. GenSight Biologics reports positive 96-week data from REVERSE Phase III clinical trial of GS010 for the treatment of Leber Hereditary Optic Neuropathy (LHON). Published 2019. Accessed 18 December 2019.

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Updated on December 3, 2020
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