Gene therapy of the human retina

Retinal gene therapy holds great promise in treating different forms of non-inherited and inherited blindness .

In 2008, three independent research groups reported that patients with the rare genetic retinal disease Leber’s congenital amaurosis had been successfully treated using adeno-associated gene therapy (AAV). [1] [2] [3] In all three studies, an AAV vector was used to deliver a functional copy of the RPE65 gene, which restored vision in children suffering from LCA. These results have been widely accepted in the field of gene therapy, and have generated excitement and momentum for AAV-mediated applications in retinal disease.

In retinal gene therapy, the most widely used vectors for adeno-associated virus . The great advantage in adeno-associated virus for the therapy is that it poses minimal immune responses and mediates long-term transgeneexpression in a variety of retinal cell types. For example, tight junctions That form the blood-retina barrier, separate subretinal space from the blood supply , providing good protection from microbes and decreasing MOST immune-mediated damages. [4]

Clinical trials

Leber’s congenital amaurosis

In 2008, three groups reported positive results of clinical trials using adeno-associated virus for Leber’s congenital amaurosis . In these studies, an AAV vector encoding the RPE65 gene was delivered via a “subretinal injection,” where a small amount of fluid is injected into the retina in a short surgical procedure.

AAV is safe in the absence, with no dose-limiting toxicities observed. Across the three trials, no serious adverse events were observed. [5] [6] Furthermore, patients in all three studies showed improvement in their visual function as measured by a number of methods. The methods used varied Among the three trials, goal included Both functional methods Such As visual acuity [1] [6] [7] and functional mobility [1] [2] [7] as well as objective Measures that are less susceptible to bias , such as the pupil’s ability to respond to light [3] [5] and improvements on functional MRI. [8]Improvements were sustained over the long-term, with patients continuing over 1.5 years. [5] [6]

UPenn trial

The University of Pennsylvania and the Children’s Hospital of Philadelphia: Jean E. Bennett, MD PhD, Albert Maguire MD, Katherine High MD, and J. Fraser Wright, PhD. In this trial, patients improved in terms of visual acuity, pupillometry, visual field, light sensitivity, mobility, and functional MRI. [1] [6] [7] [8] In the Clinical Trial Phase, children aged as young as 8 years old were treated, and reported that younger patients had better results compared to older patients. [7] A company called Spark therapeutics was spun out of the work done at the UPenn in 2013. [9]Spark was granted a “breakthrough-therapy” designation by the FDA and in November 2014 the company was running a Phase III trial of their gene therapy product SPK-RPE65. Spark planned to submit results to the FDA in 2016. [10]

Florida trial

The Florida trial was conducted under the leadership of Dr. Samuel Jacobson and Dr. William Hauswirth, with funding support from the National Eye Institute. The treatment was delivered safely, and was associated with improvements in vision. Unlike the UPenn trial, the injection was not delivered underneath the fovea, but next to it. As patients’ vision improved, they had the best vision in the injected area, rather than in the usual place at the fovea. This led to the development of so-called “pseudo-fovea” that corresponded to the treated area. [11]

Age-related macular degeneration

Following the successful clinical trials in the LCA, researchers have been developing similar treatments using adeno-associated virus for age-related macular degeneration (AMD). To date, efforts have been focused on long-term delivery of VEGF inhibitors to treat the wet form of macular degeneration. AMD is currently working with frequent injections of recombinant protein into the eyeball, these goals of these treatments are long-term disease management following a single administration. One such study is being conducted at the Lions Eye Institute in Australia [12] in collaboration with Avalanche Biotechnologies, a US-based biotechnology start-up. Another early-stage study is sponsored by Genzyme Corporation. [13]


In October 2011, the first clinical trial was announced for the treatment of choroideremia . [14] Dr. Robert MacLaren of the University of Oxford, who led the trial, co-developed the treatment with Dr. Miguel Seabra of the Imperial College, London. This Phase 1/2 trial used subretinal AAV to restore the REP gene in affected patients. [15] Initial results of the trial were reported in January 2014 as all six patients had better vision. [16] [17]

Color blindness

Main article: Gene therapy for color blindness

Recent research has shown that AAV can successfully restore color vision to treat color blindness in adult monkeys. [18] Although this treatment has been made for breakthrough photoreceptors. [19]


Physiological components in retinal gene therapy

The neural vertebrate retina, composed of several layers and distinct cell types (see anatomy of the human retina ). These agents are implicated in retinal diseases, including retinal ganglion cells , which degenerate in glaucoma, the rod and cone photoreceptors , which are responsive to light and degenerate in retinitis pigmentosa , macular degeneration , and other retinal diseases, and the retinal diseases. epithelium pigment (EPR), which supports the photoreceptors and is also implicated in retinitis pigmentosa and macular degeneration .

In retinal gene therapy , AAV is capable of “transducing” these various cell types by entering the cells and expressing the therapeutic DNA sequence. Since the cells of the retina are non-dividing, AAV continues to persist and provide a long-term history of the therapeutic DNA sequence. [20]

AAV tropism and roads of administration

AAV is capable of transducing multiple cell types within the retina. AAV serotype 2, the most well-studied type of AAV, is common in one of two routes: intravitreal or subretinal. Using the intravitreal route, AAV is injected into the vitreous humor of the eye. Using the route subretinal, AAV is injected underneath the retina, taking advantage of the potential space between the photoreceptors and RPE layer, in a short surgical procedure. Although this is more invasive than the intravitreal route, the fluid is absorbed by RPE and retina flattens in less than 14 hours without complications. [1] Intravitreal AAV targets retinal ganglion cells and a few Muller glial cells. AAV Subretinal efficiently targets photoreceptors and RPE cells. [21][22]

The reason that different ways of administration to different types of cells is being transferred (eg, different tropism ) is the inner limiting membrane (ILM) and the various retinal layers act as physical barriers for the delivery of drugs and vectors to the retinal layers . [23] Thus overall, subretinal AAV is 5-10 times more efficient than delivery using the intravitreal route.

Tropism modification and novel AAV vectors

One significant factor in gene delivery is Developing altered cell tropisms to narrow gold Broaden rAAV-mediated gene delivery and pour augmenter icts efficiency in tissue. Specific properties like capsid conformation, cell targeting strategies can determine cell type are affected qui aussi and the efficiency of the transfer gene process. Different kinds of modification can be undertaken. For example, modification by chemical, immunological or genetic changes that aids the AAV2 capsid to interact with specific cell surface molecules . [24]

Initial studies with AAV in the AAV retina have used AAV serotype 2. AAV-based serotypes and engineered AAV variants. [25]

Several naturally-occurring serotypes of AAV have been isolated that can transduce retinal cells. Following intravitreal injection, only AAV serotypes 2 and 8 were able to transducing retinal ganglion cells. Occasional Muller cells were transduced by AAV serotypes 2, 8, and 9. Following subretinal injection, serotypes 2, 5, 7, and 8 efficiently transduced photoreceptors, and serotypes 1, 2, 5, 7, 8, and 9 efficiently transduce RPE cells. . [22]

Muller glia following intravitreal injection has been used extensively, and has been used to rescue an animal model of aggressive, autosomal-dominant retinitis pigmentosa . [26] [27]

AAV and immune privilege in the retina

Importantly, the retina is immune-privileged, and therefore does not experience significant inflammation or immune response when AAV is injected. [28] Immune response to gene therapy is more important than gene therapy, and is considered a key advantage of gene therapy in the eye. Re-administration has been successful in large animals, indicating that no long-lasting immune response is achieved. [29]

Recent data indicate that the route subretinal may be subject to a greater degree of immune privilege compared to the intravitreal route. [30]

Promoter sequence

Expression in various retinal cell types can be determined by the promoter sequence. In order to restrict expression to a specific cell type, a specific tissue-specific or cell-type promoter can be used.

For example, in the rat rhodopsin gene drive the expression in AAV2, GFP reporter was found in other photoreceptors, not in any other retinal cell type or in the adjacent RPE after subretinal injection. On the other hand, if ubiquitously expressed immediate-early cytomegalovirus (CMV) enhancer-promoter is expressed in a wide variety of transfected cell types. Other ubiquitous promoters such as the CBA promoter, CMV immediate-early enhancer, and stable mutant of the chicken-actin promoter, allow stable GFP reporter expression in both RPE and photoreceptor cells after subretinal injections. [31]

Modulation of expression

Sometimes modulation of transgene expression may be essential for long-term retinal function. Different methods have been used for expression modulation. One way is using an exogenously regulatable promoter system in AAV vectors. For example, the tetracycline- inducible expression system uses a silencer / transactivator AAV2 vector and a separate inducible doxycline-responsive coinjection. [31] [32] When doxycycline , this system shows tight regulation of expression in both photoreceptor and RPE cells.

Examples and animal models

Targeting RPE

One study that was done by the Royal College of Surgeons (SCR) in rat model shows that a recessive mutation in a receptor tyrosine kinase gene, mertk results in a premature stop codon and an odd phagocytosis function by RPE cells. This mutation causes the accumulation of outer space debris in the space subretinal, which causes photoreceptor cell death . The model organism with a subretinal injection of AAV serotype 2 carries a mouse Mertk cDNA under the control of CMV or RPE65 promoters. This treatment was found to prolong photoreceptor cell survival for several months [33]and the number of photoreceptor was 2.5 fold higher in AAV-Mertk-treated eyes compared with controls 9 weeks after injection, also found debris in the subretinal space.

The RPE65 protein is used in the retinoid cycle where the all-trans-retinol is segmented to form isomerized to its 11-cis form and oxidized to 11-cis retinal before it goes back to the photoreceptor and joins with opsin molecule to form functional rhodopsin. [34] In animal knockout model (RPE65 – / -), gene transfer experiment shows that early intraocular delivery of human RPE65 vector on embryonic day 14 shows efficient transduction of retinal pigment epithelium in the RPE65 – / – knockout mice and rescues visual functions. This shows successful gene therapy can be attributed to early intraocular deliver to the diseased animal.

Targeting of photoreceptors

Juvenile retinoschisis is a disease that affects the nerve tissue in the eye. This disease is an X-linked recessive degenerative disease of the central macula region, and it is caused by mutation in the RSI gene encoding the protein retinoschisin. Retinoschisin is produced in the photoreceptor and bipolar cells and is important in maintaining the synaptic integrity of the retina. [31]

Specifically the AAV 5 vector containing the wild-type human RSI cDNA driven by a mouse opsin promoter showed long-term retinal functional and structural recovery. Also the retinal structural reliability is greatly enhanced after the treatment, characterized by an increase in the outer nuclear layer thickness. [31]

Retinitis pigmentosa

Retinitis pigmentosa is an inherited disease which leads to progressive night blindness and loss of peripheral vision as a result of photoreceptor cell death. [31] [35] [36] Most people Who Suffer from RP are born with rod cells That are Either dead or dysfunctional, so They Are Effectively blind at nighttime, since thesis are the cells responsible for vision in low levels of light. What follows is often the death of cone cells, responsible for color vision and acuity, at light levels present during the day. Loss of cones leads to full blindness as early as five years old, but can not wait until many years later. There have been multiple hypotheses about how the lack of rods can lead to the death of cone cells. Pinpointing has a mechanism for genetic correlation with this disease. In an effort to find the cause of RP, there have been different gene therapy techniques applied to address each of the hypotheses. [37]

Different types of inheritance can attribute to this disease; autosomal recessive, autosomal dominant, X-linked type, etc. The main function of rhodopsin is initiating the phototransduction cascade. The opsin proteins are made in the inner segment photoreceptor, then transported to the outer segment, and eventually phagocytized by the RPE cells. When mutations occur in the rhodopsin the directional protein movement is affected because mutations can affect protein folding , stability, and intracellular trafficking. One approach is introducing AAV-delivered ribozymes designed to target and destroy a mRNA mutant. [31]

The way this system operates is shown in an animal model that has a mutant rhodopsin gene. The injected AAV-ribozymes were optimized in vitro and used to cleave the mutant mRNA transcript of P23H (where most mutation occur) in vivo. [31]

Another mutation in the rhodopsin structural protein, particularly peripherin 2, which is a membrane glycoprotein involved in the formation of photoreptide outersegment disk, can lead to recessive RP and macular degeneration in human [35](19). In a mouse experiment, AAV2 carrying a wild-type peripherin 2 gene driven by a rhodopsin promoter was delivered to the mice by subretinal injection. The result has been detected in photoreceptor structure and function detected by ERG (electroretinogram). The result is an improvement of the photoreceptor structure and function detected by ERG. Also peripherin 2 was detected at the outer segment of the retina. 2 weeks after injection and therapeutic effects were noted as soon as 3 weeks after injection. Interestingly, a well-defined outer segment of both peripherin2 and rhodopsin was present 9-month after injection. [31]

Since apoptosis can be the cause of photoreceptor death in most of the retinal dystrophies. It has been known that these factors can be used in the treatment of the disease. Some scientists have experimented with treating this issue by injecting substituted trophic factors into the eye. One group of researchers injected the rod derived viability factor (RdCVF) protein (encoded for the Nxnl1 (Txnl6) gene) into the eye of the most commonly occurring dominant RP mutation rat models. This treatment is successful in promoting the survival of the disease. [38]AAV2 vectors with cDNA for glial cell line-derived neurotrophic factor (GDNF) may have an anti-apoptosis effect on the rod cells . [31] [39] In an animal model, the opsin transgene contains a truncated protein lacking the last amino acids of the C terminus, which causes alteration in rhodopsin transport to the outer segment and leads to retinal degeneration. [31] When the AAV2-CBA-GDNF vector is administered to the subretinal space, photoreceptor stabilized and photoreceptors increased and this was seen in the improved function of the ERG analysis. [39]Successful experiments in animals have been carried out using ciliary neurotrophic factor (CNTF), and CNTF is currently being used as a treatment in human clinical trials. [40]

AAV-based treatment for retinal neovascular diseases

Ocular neovascularization (NV) is the abnormal formation of new capillaries of already existing blood vessels in the eye, and this is a characteristic for ocular diseases such as diabetic retinopathy (DR), retinopathy of prematurity (ROP) and (wet form) age. related macular degeneration (AMD). One of the main players in these diseases is VEGF (vascular endothelial growth factor), which is known to be an inducer vessel and is known to be angiogenic. [31] In normal tissue VEGF stimulates endothelial cell proliferation in a dose dependent manner, but such activity is lost with other angiogenic factors. [41]

Many angiostatic factors have been shown to increase the effect of local VEGF. The naturally occurring form of soluble Flt-1 has been shown to reverse neovascularization in rats, mice, and monkeys. [42] [43] [44] [45]

Pigment epithelium-derived factor ( PEDF ) also acts as an inhibitor of angiogenesis . The secretion of PEDF is noticeably decreased under hypoxic conditions allowing the endothelial mitogenic activity of VEGF to dominate, suggesting that the loss of PEDF plays a central role in the development of ischemia- driven NV. One interesting clinical finding shows que la levels of PEDF in aqueous humor of human are Decreased with Increasing age, indicating indication que la Reduction May Lead to the development of AMD. [31] [46] In animal model, an AAV with human PEDF cDNA under the control of the CMV promoter prevented choroidal and retinal NV [47] (24).

The finding suggests that the AAV-mediated expression of angiostatic factors can be implemented to treat NV. [48] [49] This approach could be useful as an alternative to frequent injections of recombinant protein into the eye. In addition, PEDF and sFlt-1 may be able to diffuse through sclera tissue, [50] allowing for the potential to be relatively independent of the intraocular site of administration.


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