In the past 15 years, research in the field of retinal gene therapy has exploded. While no treatments have yet been approved for any inherited retinal dystrophies, clinical trials involving retinal gene therapy are creating hope for future therapies for afflicted patients. Consequently, retina specialists must now be able to appropriately diagnose counsel  patients with retinal dystrophies
who may be candidates for clinical trials.

This article will focus on updates in retinal gene therapy with an introduction to viral-based gene therapy, followed by a discussion of current retinal gene therapy clinical trials. The goal is to give the retina specialist a framework for evaluating and counseling these patients as they come through our clinics.  

Inherited Retinal Disease: A Brief Review

Inherited retinal diseases can be categorized by anatomic location in the eye—the macula, fovea, choroid or vitreous. Some diseases are more diffuse and affect all photoreceptors in the retina with varying degrees of insult to either rods or cones.

We categorize these diffuse diseases into two broad categories:

stationary or progressive. Stationary diseases are typically early onset, such as congenital stationary night blindness, whereas progressive diseases tend to be of later onset, such as retinitis pigmentosa (RP). Other inherited retinal diseases are part of larger syndromes or associated with systemic disease (Table 1).

Multiple clinical trials are ongoing for many of the diseases listed in Table 1. RP, the most common retinal dystrophy, has a prevalence of roughly 1:4,000.1 RP associated with the MERTK gene (for MER proto-oncogene tyrosine kinase) is an autosomal recessive form of the disease that is the subject of a retinal gene therapy clinical trial.2  

Stargardt disease is another common retinal dystrophy (prevalence: roughly 1:8,000)3 that is the focus of multiple clinical trials, including a subretinal lentivirus gene therapy trial,4 a stem cell therapy trial5 and an oral drug trial.6 Less prevalent diseases, including Leber congenital amaurosis (LCA), achromatosopia, X-linked retinoschisis (XLRS), Usher syndrome and choroideremia, are all subjects of current gene therapy clinical trials. Given these clinical trials, the need for accurate diagnosis and counseling has substantially increased.

A typical examination of a retinal dystrophy patient starts with a detailed history, with a particular focus on family history, followed by a comprehensive ophthalmologic exam. Imaging—particularly optical coherence tomography, fundus photography and autofluorescence—electrophysiologic testing and visual field testing can also play an important role in the evaluation.
Figure 1. The number of retinal dystrophy genes mapped (blue) and identified (red) from 1980 to 2014 has increased steadily, and new retinal dystrophy genes continue to be discovered. (Courtesy Stephen P. Daiger, PhD. Used with permission)

A common misconception about inherited retinal disease is that the lack of a family history argues against a genetic origin of disease. The majority of inherited retinal diseases are passed on in an autosomal recessive pattern, and often the “proband” (or affected individual) is the only reported person in a large family pedigree. Children of carriers of a recessive disease have only a one-fourth chance of having the two mutated alleles.

Similarly, the likelihood for a patient with autosomal recessive disease to pass the disease to offspring is remarkably low if the other parent is unaffected, and the prevalence of the carrier state of most retinal dystrophy mutations is quite low in the general population. Obviously, consanguinity can markedly increase the likelihood of seeing recessive disease manifest—a phenomenon known as pseudo-dominance. Eliciting this history in the clinical examination can help us better predict the inheritance pattern.

Once we establish a clinical diagnosis and an inheritance pattern, we may offer genetic testing for confirmation of disease.

Genetic Testing for Retinal Dystrophies

The key to developing possible gene-based therapies is efficient and accurate genotyping. Gene therapy is effective only when the genetic defect is identified in a given inherited retinal dystrophy. In the past 35 years, more than 200 retinal dystrophy genes have been identified and another 50 have been mapped—that is, the chromosomal location is known but the gene has not been identified (Figure 1).

Research-based or commercially available testing has its pluses and minuses. Typically, research-based testing can be at least partially funded by grants, resulting in lower patient cost. However, not all patients are candidates for grant-funded genetic testing options and results typically take much longer to receive.

Commercial l
Figure 2. In gene therapy, a viral vector carries the gene of interest into the host cell. Once this viral vector penetrates the nucleus of the host cell, the host cell machinery can mediate expression and translation of the gene into a protein.
abs often offer several-week turnaround and relatively comprehensive retinal dystrophy panels or exome sequencing, but patients’ out-of-pocket costs can be high depending on insurance coverage.
Many academic centers with ocular genetics services collaborate with genetic counselors. Outside of academic centers, some retina specialists who specialize in inherited retinal dystrophies will coordinate genetic testing and offer patient counseling. A service like InformedDNA can offer ocular genetic counselors via telemedicine.

Gene Therapy 101

Gene therapy involves use of a vector to carry the gene of interest into the host cell. Bare DNA, nanoparticles or viruses are examples of vectors, with viruses the most commonly used in clinical gene therapy (Figure 2). Existing techniques for viral vector delivery involve intravitreal and subretinal administration (Figure 3). Future techniques may include suprachoroidal and sub-internal limiting membrane techniques.

Once a viral vector is inside the nucleus, the host cell machinery can mediate the gene expression and translation into a protein product.

Adeno-associated virus (AAV) is particularly well suited for gene therapy because it is nonpathogenic, nonimmunogenic and episomal. That is, it does not integrate into the host DNA, but rather remains separate inside the nucleus where it is effectively expressed and translated into protein.

One limitation of AAV is its packaging size; this vector can only hold a 4.7-kb transgene. Scientists have taken advantage of the ability of AAV to encapsulate and deliver DNA into human cells by manipulating the virus genome to remove genes that cause disease and insert therapeutic ones. To create an AAV vector carrying a transgene of interest, the transgene is co-transfected with the rep (or replication) and cap (or capsid) viral DNA into a packaging cell, along with helper adenovirus required for replication.

Once the helper adenovirus is eliminated, the end product is the transgene of interest carried inside a viral capsid. AAV capsids can be modified (by introducing point mutations in the viral capsid genome) to make them more efficient at transduction.

The SAR422459 trial4 (previously known as StarGen) and UshStat trials8 are using lentivirus as the vector. UshStat is a gene therapy developed by Sanofi for Usher Syndrome type 1B (USHB1).9

Lentivirus is a subclass of retrovirus in which viral genome in the form of RNA is reverse-transcribed when the virus enters the cell to produce DNA. Lentivirus is believed to integrate into the genome and can infect both dividing and non-dividing cells. Lentivirus has a much larger carrying capacity than AAV (packaging capacity of 8 to 10 kb), making it the ideal vector for treating retinal genetic disorders with larger affected genes (such as the ABCA4 gene implicated in Stargardt disease).

“Replacement” gene therapy is the most common clinically relevant gene therapy. It involves replacing a protein that a cell no longer expresses due to a genetic mutation in an autosomal recessive condition. This article will focus on replacement gene therapy.

Other Forms of Gene Therapy

Multiple other forms of gene therapy exist. For example, a growth factor can be added in conditions where we do not know the genetic mutation or the conditions are genetically multifactorial. The Oxford Biomedica-sponsored RetinoStat trial for age-related macular degeneration involves expressing endostatin and angiostatin to provide sustained release of an anti-VEGF protein.7

Optogenetics (Box) involves genetically altering ganglion cells to become photosensitive. This would be useful in retinal degenerations in which the photoreceptors have already suffered extensive damage. For dominant conditions, we cannot replace a missing gene, so the option of suppression gene therapy arises, which involves small or short interfering RNA (siRNA).

Gene-editing techniques, such as CRISPR (clustered regularly interspaced short palindromic repeats), aim to genetically alter or modify DNA. This has been done in vitro and in mouse models, and has been used as a technique for controlling dominant/negative effect.

Surgical Considerations

As we gain experience from human retinal gene therapy clinical trials, we are learning that the mode of gene therapy delivery is an important determinant of both safety and potential efficacy. The majority of retinal gene therapy trials use subretinal delivery of a viral vector to efficiently transduce photoreceptors. Preclinical animal models have reported success with subretinal delivery for transduction efficiency and rescue of the condition, so logic dictates that subretinal induction would follow in human trials.

We do not yet have a viral vector that can efficiently transduce photoreceptors via intravitreal delivery in any of the inherited retinal diseases currently in human gene therapy trials. The XLRS study utilizes an AAV vector and an intravitreal mode of delivery, but given the ubiquitous intraretinal expression of RS1 in this disease, the photoreceptors do not need to be transduced.10

The LCA2 studies offered some insight into the importance of localization of the subretinal bleb. In most of the LCA2 Phase I/II trials, subretinal blebs were placed in variable locations; some involved the fovea, others were extramacular. However, some investigators have raised concerns over the mechanical trauma that foveal detachment may induce to photoreceptors.11 Patients in gene therapy clinical trials are often young, phakic and do not have a posterior vitreous detachment, all of which are certainly considerations in surgical planning.

Instrument selection for creating the subretinal bleb is also important. Options include extendible or nonextendible cannulas, probes of 38 to 41 gauge, and manual vs. automated vector delivery. The surgeon can use the viscous fluid injector system for a foot-pedal automated injection or have a second surgical assistant manually inject the vector via a syringe and tubing system.
Figure 3. Intravitreal and subretinal administration are the existing techniques for viral vector delivery. With subretinal delivery, investigators have raised concerns about the mechanical trauma that foveal detachment may induce to photoreceptors.

Another option is to create a “pre-bleb” with basic salt solution prior to injection of the vector to minimize the risk of losing the vector into the vitreous. Lifting the retina can take several attempts once the retinotomy is made with the cannula. Intraoperative OCT can help confirm the subretinal location of the vector.

Retinal tissue with degeneration and thinning is more prone to macular hole formation and iatrogenic retinal tears than healthy, thick retinal tissue. Typically surgeons try to not use air or gas to avoid bleb displacement. Postoperative supine positioning can maximize settlement of the bleb over the posterior pole. The timing for blebs to settle after surgery varies depending on the health of the retinal pigment epithelium and other factors.

Clinical Gene Therapy Trials

Active clinical gene replacement trials are targeting Stargardt disease, Usher syndrome, RP, XLRS, choroideremia, achromatopsia and Leber congenital amaurosis 2 (LCA2) (Table 2). These trials use either AAV or lentivirus as viral vectors.

Stargardt Degeneration Trials

Stargardt disease is one of the most common inherited retinal dystrophies, with a prevalence of approximately 1:8,000.3 Typical autosomal recessive Stargardt disease is associated with mutations in ABCA4 gene expressing the photoreceptor-specific ABCA4 protein, a member of the superfamily of ATP-binding cassette (ABC) transporters. Clinically, patients typically develop central visual loss as a result of progressive accumulation of lipofuscin in the RPE with the development of yellowish “pisciform” flecks and eventual macular atrophy.  

Depending on the severity of the mutations in the ABCA4 gene, there may be a wide spectrum of phenotypes, ranging from relatively mild and late-onset localized macular disease to earlier-onset diffuse cone-rod disease. A 48-week, Phase I/IIA dose-escalation trial is investigating SAR422459, a lentiviral vector gene therapy carrying the ABCA4 gene formerly known as StarGen, for the treatment of Stargardt disease.12 Eligible patients must have two pathogenic ABCA4 gene variants confirmed by segregation analysis of parental samples.

This study is investigating vitrectomy with subretinal injection of SAR422459. The primary objective is to assess the safety and tolerability of SAR422459, with the secondary objective to evaluate biological activity. After 48 weeks, patients are encouraged to continue follow-up in a long-term safety study. At this writing, 23 patients have been enrolled, and no significant changes in best-corrected visual acuity have been reported in either the treated or untreated fellow eyes. The plan is to continue enrollment in the cohort of youngest patients with early-onset Stargardt disease and evidence of rapid progression of disease (ages 6 to 26 years; all other cohorts involve patients 18 years or older).12

Usher Syndrome

Usher syndrome refers to a clinically and genetically heterogeneous group of autosomal recessive disorders which account for the most frequent cause of combined deafness and blindness in humans, with an estimated prevalence of 3–6:100,000.13

Usher syndrome has three clinical subtypes: USH1; USH2; and USH3. The severity and progression of hearing loss and the presence or absence of vestibular dysfunction distinguish these subtypes. USH1 is the most severe form in terms of the onset/extent of hearing loss and RP. The genetic mutation MYO7A (Usher 1B) accounts for approximately 30 to 50  percent of all USH1 cases.9

MYO7A (Myosin 7A) encodes an actin-based protein that performs critical motility functions in both the inner ear and retina. Patients with USH1B are born with profound neurosensory deafness, have vestibular dysfunction (that is, they often have a history of delay in walking), and develop early retinal degeneration in childhood.

A trial is investigating SAR421869 (UshStat), a lentiviral gene therapy administered via subretinal injection for the treatment of RP in patients with Usher syndrome type 1B (MYO7A gene defect). All patients must have two confirmed mutations in MYO7A.14 As of this writing, nine adult patients have been treated.15 A majority of these patients have shown an initial postoperative drop in BCVA and visual fields that improved to baseline within two weeks in early unpublished results. The vision was stable (in either the treated or untreated fellow eyes) after 48 weeks in a majority of patients. A separate cohort will provide the opportunity to extend the study to include pediatric patients ages 6 years and up.

X-linked Retinoschisis

XLRS is an X-linked disorder that affects approximately 1:5,000 to 1:20,000 individuals.16 The disease begins early in childhood, and affected boys typically have BCVA of 20/60 to 20/120 at initial diagnosis. Severe complications such as vitreous hemorrhage or retinal detachment occur in up to 40 percent of patients, especially in older individuals.16

The causative gene was identified in 1997 and named retinoschisin 1 (RS1).15 The gene codes for the retinoschisin protein, which normally provides lateral adhesion that holds retinal cells together. RS1 gene mutations alter the protein to disrupt cell structure. Without normal retinoschisin, the layers of the retina split. Affected individuals typically have early central vision loss and can develop peripheral schisis, exudate or retinal detachment. This damage often forms a “spoke-wheel” pattern in the macula as seen on clinical examination and OCT.

Research has shown that intravitreal AAV delivery can rescue the condition in mice, likely due to the diffuse expression of RS1 throughout the retina as well as the relatively increased retinal permeability that abnormal retinal morphology causes.18 This is the first replacement gene therapy trial investigating the safety and efficacy of intravitreal gene delivery for an inherited retinal dystrophy.

Ongoing are two Phase I/II studies of an intravitreal-administered AAV-RS1 vector. The National Eye Institute is evaluating three different increasing dose levels of an AAV-RS1 vector in up to 24 adult patients with VA of 20/63 or worse in one eye.19 In the second study, the biotechnology company AGTC is evaluating an AAV-RS1 vector in up to 27 patients.10  The latter study involves three initial groups of adult patients receiving increasing dose levels of the vector and will also evaluate the maximum tolerated dose level in patients 6 years and older.


Choroideremia is an X-linked recessive disorder of a genetic defect in RAB escort protein 1 (REP1) that causes degeneration of RPE and photoreceptors. It can lead to severe and diffuse chorioretinal degeneration. Patients experience gradual vision loss starting from the periphery and advancing toward the fovea. Multiple Phase I and II trials of the AAV.REP1 vector are ongoing at several sites.  

In a Phase I/II study, two patients with advanced choroideremia who had low baseline BCVA gained 21 and 11 letters in vision, respectively, despite undergoing retinal detachment.2 Four other patients with near normal BCVA at baseline recovered to within 1 to 3 letters. Maximum sensitivity measured with dark-adapted microperimetry increased in the treated eyes.

In all patients, the increase in retinal sensitivity over six months in the treated eyes correlated with the vector dose administered per area of surviving retina.20 The early improvement observed in two of the six patients was sustained at 3.5 years after treatment despite progressive degeneration in the control eyes.21

Other trials of subretinal placement of the AAV.REP1 vector are ongoing, including a Phase I/II trial Spark Therapeutics is sponsoring.22


Achromatopsia is an autosomal recessive disease that affects approximately 1:30,000 individuals and is associated with the complete loss of cone function.23 Achromatopsia is of congenital-onset and relatively stationary, with clinical findings of poor central visual acuity (usually 20/200), nystagmus, severe photophobia and complete loss of color discrimination. On electrophysiology testing, patients have nonrecordable cone-mediated responses.

The two genes most commonly associated with achromatopsia are CNGB3 and CNGA3. A Phase I/II dose-escalation study sponsored by AGTC evaluating an AAV-CNGB3 subretinal vector in patients with CNGB3 achromatopsia is ongoing at four sites in the United States.24  


The MERTK-associated form of autosomal recessive RP is very rare, with isolated patient populations identified in the Middle East and most recently the Faroe islands.2 A Phase I clinical trial utilizing an AAV2 vector with an RPE-specific promoter driving MERTK was recently completed in Saudi Arabia.2 Six patients were treated with subretinal injection of an AAV vector expressing MERTK, without any serious adverse events. Three of these patients displayed measurably improved visual acuity in the treated eye following surgery, although two of them had lost that improvement by two years.

LCA2 (RPE65-associated LCA)

Because of its early onset and the availability of multiple animal models, innovators have focused a tremendous amount of attention on developing a gene-based therapy for RPE65-associated LCA, or LCA2 (prevalence 1:100,000).25 Multiple Phase I/II trials for RPE65-associated LCA have been either completed or are ongoing. These trials have suggested that improvement in retinal function, as
measured by cone and rod sensitivity,  is detectable within the first month after treatment26-28 and may persist at one and three years.29

Despite these promising results of early visual gain, reports of visual acuity loss after treatment30 and continued photoreceptor degeneration at three years have emerged.31 Although these findings of progressive degeneration are somewhat discouraging, they do provide context for an educated and realistic interpretation of findings from these exciting Phase I/II trials as we move into treatment trials for other inherited retinal disorders.  

The recently completed Phase III trial of SPK-RPE65 for treatment of RPE65-associated LCA reported that treated patients displayed improved sensitivity to dim light compared to controls (P<0.001) with no significant difference in visual acuity between the two groups.27 The 31 subjects were randomized 2:1 to an early treatment arm or a one-year treatment- delayed arm.27 Both eyes received a subretinal injection of 300 μL of AAV, with the second eye treated within 18 days of the first.

The primary endpoint for this trial was mobility testing in an obstacle course with one eye patched. Treated patients scored better than controls (P<0.001), meaning that these treated patients could navigate the maze in lower-light conditions. The secondary outcome was full-field light sensitivity, which was done with both eyes open.

The trial reported no serious adverse events. All ocular events were mild. They included transient elevated intraocular pressure in four subjects, cataract formation in three, retinal tears that resolved after laser in two subjects and transient mild eye inflammation in two subjects. Spark Therapeutics has filed a Food and Drug Administration application for approval of this therapy. That could pave the way for future retinal gene therapies and certainly raise awareness of the need for accurate clinical diagnosis of retinal dystrophies and genetic confirmation of disease.27

Optimizing Vectors, Delivery

Groups are also continuing to work on optimizing vectors for “potency” to possibly increase the therapeutic effect of gene transfer.32 Some investigators believe that earlier treatment in these progressive retinal dystrophies may offer the best chance of sustained visual recovery. Phase I/II trials have shown no direct correlation between patient age and treatment response, although they did report less dramatic improvements in retinal sensitivity in younger patients who had the greatest preservation of retinal structure.30

The mechanism for surgically delivering gene therapy to the retina is under much discussion because of the potential trauma subretinal injections may cause, particularly those involving the macula. Some of the phase I/II LCA trials suggested that patients lost visual acuity and retinal thickness after subfoveal injections, potentially due to mechanical trauma to the fovea from inducing a retinal detachment.11

Keep in mind that these trials involving subretinal injections are targeting only cells in the region of the surgically induced subretinal bleb, which make up a small percentage of the entire retina (gene therapy clinical trial bleb sizes range from 150 μm to 450 μm).

Zones of retina treated, as well as viral vector dosing, play important roles in the long-term restoration of function. We may yet learn that concomitant neuro-protectant treatments are also going to be useful, if not mandatory, in treating inherited retinal degenerative disease.  

Future Trials

AGTC expects to begin enrollment soon of a Phase I/II dose-escalation study for treatment of CNGA3-achromatopsia with AAV (using the same AAV vector and promoter as used in the CNGB3 study).33 AGTC is also developing an AAV-RPGR vector for X-linked RP for which it plans to submit an investigational new drug application to the FDA in 2017.34


The most thoroughly studied genetic retinal disease at this point remains RPE65-associated LCA2, with multiple Phase I/II trials as well as one Phase III trial completed and one FDA application underway.

Although most phase I/II trials for LCA2 show initial improvement in retinal sensitivity in patients after gene therapy, these improvements were modest even in participants with relatively mild retinal degeneration  and failed to protect against ongoing degeneration,30 suggesting that we still have much room for improvement in the field.

Research into new optimized vectors for therapeutic efficacy and longevity needs to continue. From a clinical standpoint, we still do not fully understand which patients may benefit most from therapy and how therapeutic intervention will alter the natural history of retinal degeneration and progression of vision loss. From a surgical standpoint, more attention is being placed on optimal delivery to minimize mechanical trauma and perioperative inflammation.

Retinal gene therapy has advanced eons in the past 10 years. We will likely see FDA approval in the near future for the first viral-based retinal gene therapy for LCA2. With innovations like optogenetics we can imagine a future where multiple different diseases can be treated with a larger window of opportunity for therapeutic effect. While exciting to the clinical community, these advances will be even more attractive to our patients who, until very recently, have been told at yearly follow-ups, “There is nothing that can be done.” We are finally at a point where we can offer realistic hope.  RS

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