Wednesday, 4 April 2012

New Gene Therapy that May Correct a Common Form of Blindness


In January 2012, researchers at the University of Florida developed a new gene therapy method that can potentially treat a common form of blindness, X-linked retinitis pigmentosa (XLRP). XLRP is one of the most common causes of hereditary visual loss. This genetic defect results in gradual degradation of photoreceptor cells which are responsible for absorption of photons (Photoreceptor cell 2011), initiating signal transduction and stimulating optic nerves. The signal reaches the brain where our visual perception is constructed (Reece et al. 2011). The loss of these structures results in "initial loss of peripheral and night vision, ... then blindness".
 
Figure 1: Diagram of the human eye with a schematic enlargement of the retina.
Webvision 2011, viewed 21 March 2012, http://webvision.med.utah.edu/book/part-i-foundations/simple-anatomy-of-the-retina/

XLRP is similar to X-linked progressive retinal atrophy (XLPRA) in canines. Both have the same genetic mutation site and disease spectrum. In this study, canines with XLPRA were separated into 2 groups.

Figure 2: Canines with XLPRA used in the study were separated into two groups. The control group was left untreated, while the experimental group was subjected to gene augmentation therapy.

Gene augmentation therapy involves introduction of a normal copy of the functional allele into photoreceptor cells. This produces the normal photoreceptor protein when the gene is expressed. The gene is transferred into cells using Adeno-associated viruses, which enters the cell via endocytosis. In addition, the researchers included a promoter to facilitate the transcription of the gene. These viruses were then injected into the subretinal area of the canines at 28wk, well before the start of photoreceptor loss, and "monitored to 77wk, well after the start of degeneration" (Beltran, 2012, pp. 2133). 

Figure 3: Gene augmentation therapy
Strachan T, Read AP 1999, Human Molecular Genetics, 2nd edition, New York: Wiley-Liss, New York

Photoreceptor degeneration was monitored by measuring the thickness of the outer (photoreceptor) nuclear layer (ONL). The outer nuclear layer consists of cone and rod (photoreceptor) granules which are connected to the photoreceptors. Photoreceptor degeneration leads to a thinner ONL.
Comparison between the 2 groups showed that gene augmentation therapy successfully prevented photoreceptor degradation within the treatment area. ONL was thicker "on the treated side of the subretinal injection area boundary compared with the untreated side" (Beltran, 2012, pp. 2134). However, there was still ONL degeneration outside this region.
                                                                                                         
     Without treatment 



 

With treatment





Figure 4: ONL thickness of canines in the control group and canines in the experimental group.
Beltran, WA et al 2012, 'Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa', Proceedings of the National Academy of Sciences, vol. 109, no. 6, pp. 2132-2137


Further testing showed that "mislocalization of rod and cone opsins, a feature of the disease... was reversed" (Beltran, 2012, pp. 2135).  Opsins are membrane-bound G protein-coupled receptors and mislocalization can affect vision (Opsin 2011).


The success of this study is significant as there is currently just one treatable human retinal genetic disease (Beltran 2012). Previously, retinitis pigmentosa was classified as incurable. Given the similar genetic mutation and disease spectrum of XLPRA and XLRP, there is great potential for progression into human clinical trials (Beltran 2012). However, there are still several complex and costly obstacles to overcome before this is translated to clinical treatments, but once these obstacles are overcome, "it has great potential to change lives". This success also further proves that gene therapy is a highly viable option for future treatment of genetic diseases. 

"Imagine that you can't see or can just barely see, and that could be changed to function at some levels so that you could read, navigate, maybe even drive -- it would change your life considerably"      
-William W. Hauswirth, professor of ophthalmology in UF College of Medicine             


References

Beltran, WA et al 2012, 'Gene therapy rescues photoreceptor blindness in dogs and paves the way for treating human X-linked retinitis pigmentosa', Proceedings of the National Academy of Sciences, vol. 109, no. 6, pp. 2132-2137
Opsin, 2011, viewed 18 March 2012, http://en.wikipedia.org/wiki/Opsin
Photoreceptor cell, 2012, viewed 19 March 2012, http://en.wikipedia.org/wiki/Photoreceptor_cell
Reece, Meyers, Urry, Cain, Wasserman, Minorsky, Jackson, Cooke 2011, Campbell Biology, 9th edition, Pearson, Australia
Strachan T, Read AP 1999, Human Molecular Genetics, 2nd edition, New York: Wiley-Liss, New York
University of Florida Health Science Centre 2012, Researchers develop gene therapy that could correct a common form of blindness, ScienceDaily, viewed 18 March 2012, http://www.sciencedaily.com/releases/2012/01/120123163412.htm
Webvision 2011, viewed 21 March 2012, http://webvision.med.utah.edu/book/part-i-foundations/simple-anatomy-of-the-retina/
      

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