By Elizabeth Ach (Scripps College) and Tianna Sheih (Scripps College) [Edited by Lars Schmitz, as part of BIOL 167 “Sensory Evolution”, an upper division class at the W.M. Keck Science Department. Written for educational purposes only.]
Retinitis pigmentosa is a disease that causes progressive vision loss due to age-related macular degeneration. The disease slowly attacks parts of the retina, including the rods and cones, and the retinal pigment epithelium (RPE). Essentially it breaks down photoreceptors that are responsible for capturing images from the vision field. For some, it can completely destroy the outer retinal photoreceptor layer. For most, the disease begins by attacking the rods, which are primarily triggered by dim lighting because of their outer location. When sensitivity to light begins to degenerate, night vision ability also begins to degenerate. Rods are also responsible for peripheral vision. For most patients, cones are the second to be affected. Because cones are located more centrally and are responsible for color perception and sharp images, when cones begin to degenerate, patients lose ability to perceive color. The amount of time it takes for this deterioration to occur can range between people, but the majority becomes legally blind by the age of 40.
Retinitis pigmentosa affects approximately 1 in every 4,000 people in the United States and is related to a family history of the disease. So, how are people affected by it? The gene related to retinitis pigmentosa can be passed on from parent to their offspring in three different ways. More importantly, is how exactly this gene causes retinitis pigmentosa. When the dysfunctional gene is passed on to offspring, incorrect information on how to express proteins needed for photoreceptors is passed on as well. This makes for rods and cones with abnormal proteins, which in turn causes a slow deterioration in these cells (Vorvick 2012).
Sounds horrible, right? But don’t despair – repair is here! Scientists have found a way to restore sight in people who are completely blinded by retinitis pigmentosa. Previous approaches to treating this disease have been (1) epiretinal implants, (2) subretinal approaches, and (3) suprachoroidal implant. Epiretinal implants are electrode rays surgically placed to sit directly within the retinal ganglion cells. Subretinal approaches include placing microchips underneath the retina to act as photoreceptors. Lastly, suprachoroidal implants are placed above the vascular chord.
In previous attempts to cure this disease, many researchers have experimented with electrical chips that were placed in the hopes of acting as photoreceptors. In one particular study, performed by Douglas Yanai et al. in 2007, 4 x 4 retinal prostheses containing 16 platinum electrodes were placed in three different patients who had been diagnosed with retinitis pigmentosa. The chip was placed within the retina and its wires were run through the temporal bone. A larger wire was surgically placed along the skull and went into the orbit. The idea was to connect the chip to a computer and internally stimulate photoreceptors using electrical signals. The results of this experiment illustrated that some aspects may have been effective, but others were not. Only 50% of patients were able to recognize a capital letter “L”, and even fewer (40%) were able to identify a moving object (Yanai 2007). The study helped pave the way for future scientists to further investigate retinitis pigmentosa.
Recently, in one 2011 clinical trial conducted by Eberhart Zrenner et al., three patients were implanted with a subretinal implant that contained a microphotodiode array (MPDA) with 1500 individual light-sensitive elements. These photodiodes are able to simultaneously capture an image several times per second, which are then delivered as voltage pulses to adjacent groups of bipolar cells in the eye. This implant, made from only 20 µm thick polyimide foil, also has a test field with 16 electrodes meant for direct electrical stimulation. This test field was added as an alternative to the MPDA and was meant to be an in-depth study of the efficacy of pulses with different shapes and polarities (Zrenner et al. 2011).The patients were selected because they had all become blind due to hereditary retinal degenerations. Patient 1 and Patient 2, a 40 -year-old male and a 44-year-old male respectively, suffered from retinitis pigmentosa. Patient 3, a 38-year-old female, suffered from choroideraemia. Choroideraemia is very similar to retinits pigmentosa, it is an X-linked recessive disease that affects the choroid and photoreceptors (MacLaren 2014). All three had possessed good central vision prior to the onset of their symptoms but they had lost their reading ability at least five years before beginning these clinical trials.
Results showed that all patients were able to detect single electrode, single pulse stimulation which consisted of 6 millisecond pulses that were about 20-60 nC per electrode. All patients were also able to differentiate horizontal lines from vertical lines. Unfortunately, Patient 3 was found later on to lack abilities that both Patient 1 and 2 embodied. Patient 3 was unable to identify letters that appeared through simple pulsing electrodes, whereas patients 1 and 2 were able to distinguish a “U” from an “I”. In a second part of testing the device, light pattern perception was tested. Researchers used 1 to 20 Hz with a pulses at 1-4 milliseconds. Next, researchers let there be light. They tested light perception using two tasks. The first, a BaLM-test, was used to test perception of movement using random dot patterns. The second test, experimented with spatial resolution and grid patterns. Only Patient 2 was able to correctly recognize the orientation of such grid patterns, but all patients were able to detect light (Zrenner 2011). Responses from patients are shown below in Figure 2.However, that doesn’t mean to say that everything they’ve done is perfect. In Zrenner’s clinical trial, only three patients were tested and more testing would be needed in order to provide conclusive evidence. Variables related to the patients’ medical history may be responsible for their varied results and more people would be needed in order to confirm the microchips’ effectiveness in treating age-related macular degeneration. Additionally, Zrenner mentioned that the location of where the chip was placed inside the retina was changed for each patient. Consequently, researchers need to investigate the effects of varying placement and the impact that may have on restoring sight. Another area that could use some improvement is minimizing the size of the equipment connected to the microchip (Figure 3). The microchip is dependent on a power source that needs to be carried on a strap placed on the patient’s neck. This may prove to be cumbersome and finding an alternative method would greatly benefit the usefulness of the microchip.
So what’s happening now? In more recent years, researchers have been able to further restore vision in retinitis pigmentosa patients. In one 2013 study conducted by Singh et al., researchers aimed to reconstruct a retinal layer with transplanted rod precursor cells. These cells, harvested from 3D murine embryonic stem cell cultures, were transplanted into mice that were homozygous for the retinal degeneration allele. Results showed that animals that began with zero rod function were able to regain some visual function… so no more three blind mice. The transplanted rod cells were able to reform an anatomically distinct and appropriately polarized outer layer to replace the one that had been damaged by the disease. These cells were also able to connect with host neurons located downstream. Overall, the transplanted cells developed into mature rods that were able to facilitate the transmission of light-evoked responses all the way to the brain (Singh 2013). Amazing!
What does this mean in the bigger scheme of things? Studies like the ones described above are continually advancing medical research and providing more practical solutions to visual degenerative disease. Scientists are continuing to fix visual impairment and to help the many people who suffer from these diseases. Research on this particular disease could help improve treatments and cures for other diseases that attack photoreceptors in the eye. While research discussed above focuses on vertebrate eyes, retina and photoreceptor structures vary significantly between phyla. One possibility would be to look more closely at the evolution of retina structure and photoreceptors, giving us a broader understanding of how to pursue a solution. For example, cephalopods differ substantially from vertebrates in that their nerve fibers are routed behind the retina whereas vertebrates have nerve fibers that route through the retina. Vertebrates have a blind spot because the nerve fibers block some light from coming through, but cephalopods do not have this same issue. There are also some differences how retinal cells are “wired”. Although recent investigations have made exciting advances, there are still many possibilities for discovery and improvement. Looking at these structural differences could help us to find better solutions, helping those who are affected by visual degeneration.
MacLaren, R. E. et al. 2014. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet 383 (9923),1129-1137. (DOI 10.1016/S0140-6736(13)62117-0)
Singh, M. S. et al. 2013. Reversal of end-stage retinal degeneration and restoration of visual function by photoreceptor transplantation. Proc Nat Acad Sci 110 (3), 1101-1106. (DOI 10.1073/pnas.1119416110)
Vorvick, L. J. 2012. Retinitis Pigmentosa. United States National Library of Medicine.
Yanai, D. et al. 2007. Visual performance using a retinal prosthesis in three subjects with Retinitis Pigmentosa. Am J Ophthalm 143 (5), 820-827. (DOI 10.1016/j.ajo.2007.01.027)
Zrenner, E. et al. 2011. Subretinal electronic chips allow blind patients to read letters and combine them to words. Proc Roy Soc B 278 (1711), 1489-1497. (DOI 10.1098/rspb.2010.1747)