Running Head: IMPROVING CENTRAL BLINDNESS WITH GENE THERAPY 1

Widening the Horizon: Improving Central Blindness with Gene Therapy

Ashley N. Mattingly

University of Kentucky
IMPROVING CENTRAL BLINDNESS WITH GENE THERAPY 2

Abstract

Stargardts is a form of a genetic disease that attacks the retina of the eye. It is a form of

macular degeneration that causes a progressive loss of central vision while there is no destruction

to peripheral vision. This loss of vision begins in the mid to late stages of youth. Research has

found that there may be a way to regenerate the damaged cells by altering the genome. There are

various ways to attempt to accomplish this including two types of treatment called gene and cell

therapy. Cell therapy uses stem cells while gene therapy uses modified viruses to modify the

DNA in the damaged cells. Cell therapy has been used to halt the progression of the disease and

seems promising for the use on youth. However, gene therapy has the potential to erase the

mutations causing cells to be damaged entirely. With different types of gene therapy, the most

promising type for Stargardts is to use the HIV based lentivirus that can attack cells that do not

divide, like the ones in the retina. Although the lack of testing of the lentivirus raises concerns as

well as the fact the virus is HIV based, it is my recommendation to use it to modify the genome.

On children, however, it is my recommendation to use cell therapy to stop the disease before its

progression is noticeable, and due to the fragility of the eye in old age, there should be an age

limit for gene therapy on Stargardts.

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Introduction

The research I have conducted has focused on the progressive genetic eye disorder

Stargardts. Studies have found ways to potentially reverse the effects of Stargardts. Through

injections of stem cells in cell therapy and tampered viruses in gene therapy, there is a possibility

of rewriting the genome of the eye. However, both options have setbacks. Although trials have

gone well, there is a threat of the unknown with gene therapy and a rather low success rates with

cell therapy. This recommendation report will go into detail the possibilities of reversing

Stargardts as well as the potential setbacks.

History of Stargardts Figure 1

Stargardts is a genetic disorder of the eye

that causes the death of photoreceptor cells

in the center of the retina beginning at a

young age. Stargardts is a progressive

disease causing a gradual loss of central

vision over time without correction with lenses being an

option. However as central vision disappears almost entirely,

peripheral vision remains normal. The

destruction of the central vision is shown by a Figure one presents the progression of
Stargardts through the bright copper
coloring.
bright copper specs or area in the central eye

shown in figure 1. This disease comes from a recessive mutation in the genome affecting seven

areas of the ABCA4 and two of the PROM1. The effects of these recessive mutations appear in

juveniles as young as elementary ages. Stargardts is one of the most common inherited eye

disease and concerns one in ten thousand people.

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The Environment of the Eye

The eye is an optimal choice for cell treatment because of the stable cell population. This

provides convenience and a control type environment for viral injections. As the individual

reaches the age of forty-four, the environment of the eye may begin to change. As fragility

increases in general in the body with age, in the eye there is a risk of age related macular

degeneration and cataracts developing. This could conflict with treatment for Stargardts and

result in undesired repercussions.

Recommendation 1

Due to the facts and the facts above, I recommend performing the treatment for

Stargardts as soon after the diagnosis as possible. This way, the disease has minimal effect on

the child. Therefore, the individual will be able to be the least hindered by the disease for the

shortest possible period.

Cell Therapy vs Gene Therapy

There are multiple types of treatment for Stargardts, but the two most notable is gene

therapy and cell therapy. Gene therapy consists of taking a virus and altering its DNA. The goal

of gene therapy is to allow the virus to use the defected cell as a host. Here, the tampered virus

will replace its altered DNA with the defected DNA. From there, the DNA can be coded so the

mutations in the sections of the genome that cause Stargardts are no longer existent.

Cell therapy requires the injection of stem cells into the retina. Much like the viruses in

gene therapy, the stem cells have DNA that can be coded. Regenerating the cells in the eye with

cell therapy has halted the progression of Stargardts at the ages seventeen to eighteen. The

problem with this technique is that it will not reverse the damage that has already been done. By
IMPROVING CENTRAL BLINDNESS WITH GENE THERAPY 5

the age of seventeen to eighteen, many individuals have eye sight poor enough to result in the

loss of their license and reading skills.

Recommendation 2

Due to the setbacks of cell therapy in comparison to gene therapy, my recommendation is

that the procedure in correcting Stargardts be purely gene therapy after the age of thirteen, when

side effects tend to become increasingly noticeable. If Stargardts is

Figure 2
diagnosed prior, cell therapy should stop

the progression of the disease.

Types of Gene Therapy

Within gene therapy, there are

different types of viruses that can use the

defective genes as a host. Two viruses

used for Stargardts therapy are the

adenovirus and the lentivirus

demonstrated in figure 2. Since the cells

within the retina are unable to divide, the lentivirus is a An infographic demonstrating gene
therapy with lentiviruses.
very important key to gene therapy for Stargardts. This

virus, unlike the adenovirus, can attack nondividing cells and have a long-term affect.

However, the controversy of using the lentivirus is based off the combination that it is a

HIV based virus and the testing for it so far has been limited. However, in years of limited

studies on mice, pigs, and people there have been no repercussions of the lentiviruss use.

Recommendation 3
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Although the limits of the testing and being HIV based, I recommend the lentivirus to be

used over the adenovirus because it is tailored to thrive in the environment the eye presents and

seems to be more promising.

Endnotes

In conclusion, Stargardts is a genetic eye disease that affects many people worldwide.

And although various breakthroughs have been made in different tests, the most promising

results lie in addressing the problem early, using gene therapy to their advantage, and relying on

lentiviruses to breakthrough a form of macular degeneration causing the loss of vision.

IMPROVING CENTRAL BLINDNESS WITH GENE THERAPY 7

References

Chulay, J. D. (2015, June). Retinal gene therapy moving closer to clinical reality. Ophthalmology

Times Europe. pp. 37-40.

Colella, P., Trapani, I., Cesi, G., Sommella, A., Manfredi, A., Puppo, A., & ... Auricchio, A.

(2014). Efficient gene delivery to the cone-enriched pig retina by dual AAV

vectors. Gene Therapy, 21(4), 450-456. doi:10.1038/gt.2014.8

Dalkara, D., Goureau, O., Marazova, K., & Sahel, J. (2016). Let There Be Light: Gene and Cell

Therapy for Blindness. Human Gene Therapy, 27(2), 134-147.

doi:10.1089/hum.2015.147

Eksandh, L., Ekstrm, U., Abrahamson, M., Bauer, B., & Andrasson, S. (2001). Different

clinical expressions in two families with Stargardt's macular dystrophy (STGD1). Acta

Ophthalmologica Scandinavica, 79(5), 524-530. doi:10.1034/j.16000420.2001.790520.x

GENE THERAPY CLINICAL TRIAL UNDERWAY FOR STARGARDT'S DISEASE.

(2011). Journal of Visual Impairment & Blindness, 105(7), 443.

K. Thiran Jayasundera, M.D., FACS, FRCSC, FRANZCO Stargardt Research. (2015).

[photographs and visual acuities of patients seen at the University of Michigan ].

Retrieved from http://kellogg.umich.edu/bios/jayasundera.stargardt.research.html

IMPROVING CENTRAL BLINDNESS WITH GENE THERAPY 8

Kong, J., Kim, S., Binley, K., Pata, I., Doi, K., Mannik, J., & ... Allikmets, R. (2008). Correction

of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene

therapy. Gene Therapy, 15(19), 1311-1320. doi:10.1038/gt.2008.78

Lions Eye Institute., Eye Diagram. (2017).

[diagram of the eye ]. Retrieved from https://www.lei.org.au/services/eye-health-

information/eye-diagram/

Nentwich, M. M., & Rudolph, G. (2013). Hereditary retinal eye diseases in childhood and youth

affecting the central retina. Oman Journal Of Ophthalmology, 6(4), S18-S25.

doi:10.4103/0974-620X.122290

Treatment for Diseases of the Retina and Vitreous. (2016). [Image of Stargardts in the eye].

Retrieved from http:// http://www.scottpautlermd.com/stargardt-disease/

Zhang, X., Ge, X., Shi, W., Huang, P., Min, Q., Li, M., & ... Gu, F. (2014). Molecular Diagnosis

of Putative Stargardt Disease by Capture Next Generation Sequencing. Plos ONE, 9(4),

1-9. doi:10.1371/journal.pone.0095528