Trying to see clearly

by Casey Valentine

Macular dystrophies (MDs) are acknowledged as inherited retinal disorders which cause loss of vision due to the macula’s deterioration (1). Macular dystrophies cause irregularities that damage the macula and therefore affect the central vision (1). A common form of macular dystrophy is Stargardt disease which results from a mutation in the ABCA4 protein and is autosomal recessive. (2).

ABCA4 is the ATP-binding cassette transporter gene and is crucial for transporting vitamin A derivatives out of the visual cycle. Too much vitamin A will cause a toxic build-up and damage to the eye which resultsin blindness. ABCA4 is recognised as the most common cause of retinal degeneration in Mendelian inheritance.

A study performed by A. Auricchio et al. entitled “Gene Therapy of ABCA4-Associated Diseases” aimed to reveal the best treatment options for those affected by ABCA4-associated diseases (3). The study revealed that direct gene replacement therapy was the most promising treatment option as all ABCA-4 associated diseases are autosomal recessive and therefore the addition of a functional gene would re-establish visual function.

The main strategies considered for the transport of the genetic material included viral vectors and non-viral vectors. As the ABCA4 gene has a large sequence of 6.8kb, there was a challenge in finding the most appropriate vector as it would require a transport vector that has a large cargo capacity and effective photoreceptor (PR) capability (3).

The best nonviral strategy described included a polylysine-based compacted DNA nanoparticle (NP) CK30-NP, which showed improved effectiveness in ocular gene transfer. This method is beneficial as it allows the vector to enter the nucleus of cells and has the capacity for plasmids up to 20kb’s in length. (3) Moreover, a test performed on a homozygous null mutation of ABCA4 in a mouse model of Stargardt disease, indicated that 8 months after an injection of CK30-NP, there was improved recovery of dark adaptation and reduced lipofusion accumulation (3).

The viral vectors examined in this study were based on adeno-associated viruses (AAV) and lentiviral vectors. Dual AAV strategies including trans-splicing, overlapping and hybrid dual-vector strategies were investigated. It was indicated that dual AAV trans-splicing and the hybrid F1 phage genome (AK) vectors showed promising results in mouse models with Stargardt disease. This method allowed the vectors to carry and transport the ABCA4 protein to the photoreceptor cells. This indicated a favourable strategy for the treatment of ABCA4-related disorders. Many trials were thus performed using this model which proved that retinal therapy using the dual AAV model is safe and effective for treatment in ABCA4. The other viral vector considered was lentiviral vectors. Lentiviral vectors were considered beneficial as a vector for ABCA4 as it has the capacity to carry large expression cassettes as that of the ABCA4 protein. Lentiviral vectors are also able to transport genes steadily into its target genome. Lentiviral vectors however did not show much improvement for the treatment of ABCA4 in rodent models which caused this method to be less reliable. However, studies done in non-human primates, such as macaques, showed better improvement. The studies performed in non-human primates indicated that was an improvement in the affected photoreceptors. Although this is promising for possible lentiviral vector usage in humans, more research would need to be done to ensure its safety and efficacy.

This study showed that although extensive research is being done to find the best treatment for ABCA4-related disorders, more still needs to be investigated before a definite decision can be made. It is important to continue research in this area especially as ABCA4 disorders are the most common retinal disorder of mendelian inheritance.


  1. Rahman N, Georgiou M, Khan KN, Michaelides M. Macular dystrophies: clinical and imaging
    features, molecular genetics and therapeutic options. Br J Ophthalmol. 2020;104:451–60.
  2. Roberts LJ, Nossek CA, Greenberg LJ, Ramesar RS. Stargardt macular dystrophy: common
    ABCA4 mutations in South Africa–establishment of a rapid genetic test and relating risk to
    patients. Mol Vis [Internet]. 2012 Feb 1 [cited 2022 May 11];18:280–9. Available from:
  3. Auricchio A, Trapani I, Allikmets R. Gene Therapy of ABCA4-Associated Diseases. Cold Spring
    Harb Perspect Med [Internet]. 2015 May 1 [cited 2022 Sep 16];5(5). Available from:

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