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Gene therapy: The future is now

Optometry Times JournalApril digital edition 2020
Volume 12
Issue 4

Studies allow optometrists to tell patients that there is hope.

gene therapy

The eye is a good place for gene therapy because of its accessibility, size, immune privilege, and presences of cells that do not divide during life. A number of gene-therapy trials are underway for inherited retinal diseases, including those that are rare or commonplace, with promising results.

It was only a distant hope as recently as a few years ago that scientists would be able to manipulate the human genome to cure or treat systemic and ocular diseases. After all, it was only 2003 when the announcement came that the Human Genome had been fully sequenced.1

That has changed in the last several years. Eye care received tremendous news when Spark Therapeutics announced in December 2017 the Food and Drug Administration (FDA) approval of Luxturna (voretigene neparvovec-rzyl).


Luxturna is the first FDA-approved gene therapy for a genetic disease, Leber’s congenital amaurosis (LCA). As of this writing, it is the first and only pharmacologic treatment approved for any inherited retinal disease (IRD).

Related: Macular diseases: Emerging best practices for diagnosis, management and follow-up protocols

Luxturna’s mechanism of action is to repair the defective biallelic RPE652 gene mutation. The RPE65 protein is a vital component of the visual cycle. When light impinges on the photoreceptors in the retina, 11-cis-retinal (a form of vitamin A) is converted into all-trans-retinal.

A series of reactions occurs, ultimately converting the original light hitting the photoreceptors into an electrical signal carried by the axons of the ganglion cells. RPE65 is vital in the cycle because it helps convert all-trans-retinal back to 11-cis-retinal so the visual cycle can begin again.

The University of Michigan W.K. Kellogg Eye Center announced in early 2019 that the first two cases treated with Luxturna were a success.3 Bilateral treatment was accomplished over several weeks in two children. Results of the treatment as far as visual gain and slowing or stopping the progression of LCA is not yet available.

Related: The myopia epidemic: Are new therapies in sight?

Gene therapy and the eye
Eyecare practitioners and their patients are fortunate that the human eye is a perfect place for initial gene therapies to be trialed and, now, come to fruition.

Firstly, the eye and specifically the retina is easy to access and view with the instruments and surgical techniques available. It is also a small area relative to other organs.

The most import factor in the eye is “immune privilege.” This essentially means that the response to inflammation in the eye is muted compared to other tissues in the body. The eye limits the inflammatory immune response so that vision isn’t harmed or compromised by swelling and other normal inflammatory responses.

Related: Hope in the time of COVID-19

Another factor is that the rods and cones of the retina do not divide during life, so the genetic therapy does not have to be concerned with new generations of cells.

There are many ongoing studies, some in Phase I/II and III, for IRDs.4 It is a fertile area of research because often these diseases involve defects in just one gene, unlike many other common ocular diseases such as glaucoma and macular degeneration. Three main delivery systems are now in use in studies in the United States and around the world.

AAV vector delivery
Luxturna achieves its goal of inserting the functional gene into the defective cell genome using a process called adeno-associated virus (AAV) vectoring.4 This technique effectively involves inserting the functional gene into the AAV.

Related: Comanaging intraocular lens power calculations

In Luxturna, AAV2 is used. Injection under the retina allows the virus to infect all the relevant cells and introduce the wild-type RPE65 gene into the nucleus to be expressed properly.

The majority of gene therapies under investigation utilize this technique. The immune-privileged nature of the eye prevents the vecto from disseminating systemically and the immune system from reacting to its components.

The main disadvantage of AAV vectoring is the small amount of DNA it can carry.

Related: Pediatric headache: The vital role of the optometrist

CRISPR-Cas9 genetic-editing technique
CRISPR is an acronym for “clustered regular interspaced short palindromic repeats.” Imagine having a “GPS-quality” technique to target a specific genetic defect, remove it, and replace it with the proper gene. That is essentially how CRISPAR-Cas9 works.6

A scaffold of RNA binds to DNA at a precise complementary location that is predetermined, and the pre-designed sequence “guides” Cas9 to the right part of the genome. The Cas9 protein is an enzyme that cuts foreign DNA. The RNA guiding mechanism ensures that the Cas9 enzyme cuts at the correct point in the genome.

Scientists can use the DNA repair machinery to introduce changes to one or more genes in the genome of a cell of interest. Because CRISPR has a strand of RNA that guides the target DNA into the enzyme, the system is extremely precise, while other gene-editing methods work off a much rougher map. Studies are ongoing using this method to genetically treat IRDs.

Related: 10 new treatments in eye care

Stem cell gene therapy
Stem cell therapy involves the use of living cells to deliver therapeutic genes into the body to correct genetic defects and tissue that has died or become non-functional.7

Lymphocyte or fibroblast stem cells are removed from the body, and the therapeutic gene is introduced into the cell. Alternatively, embryonic stem cells can be harvested. In the laboratory, the cells are genetically modified. After demonstrating that they produce the proper protein or chemotactic factor(s), they can grow and multiply and, finally, are infused back into the patient.7

The addition of the therapeutic genes outside the patient allows the process to be well controlled. Researchers can select and work only with those cells that both contain the correct gene and produce the therapeutic agent in sufficient quantity.

There are ongoing studies, mostly in Phase I and II, for conditions such as dry macular degeneration, retinitis pigmentosa (RP), choroideremia, and Stargardt disease.7

Related: How to manage the angle closure spectrum

Studies show the way
There are dozens of studies ongoing at various institutions worldwide trying to develop treatments or cures for a variety of inherited eye diseases, including those that are rare or commonplace.

The highlighted studies just scratch the surface of this fertile field. Some are in Phase III trials, which means that they may be just a few years from clinical practice. Others are more blue sky but paint the picture of what might be achieved with gene therapy.

Related: Companies offer CE, other resources amid coronavirus pandemic

Choroideremia gene therapy
Choroideremia is an X-linked disease affecting about 50,000 people, almost exclusively males, in the U.S. It occurs in childhood and results in progressive vision loss, first affecting night or low-light-level vision. It is caused by a lack of RAB escort protein-1 (REP-1), produced by the CHM gene. This protein allows the removal of waste from photoreceptors, allowing them to stay healthy.

Phase III trials are now underway in the U.K. In Phase I/II trials, visual acuity was maintained or improved in 90 percent of trial participants. The techniquesused is AAV-healthy copies of the CHM gene are delivered to affected cells, compensating for the mutated copies.8

Retinitis pigmentosa
RP is a complex disease with more than 70 known genes and thousands of genetic defects. About 2 percent of patients with RP have the RPE65 defect that is being treated with Luxturna for LCA. Phase I and II studies by Spark Therapeutics have demonstrated improvement in acuity in small cohorts.

A French Company, Horama, started Phase I/II clinical trials also using the AAV2 approach for people with RP caused by PDE6B mutations.9 The three-year trial will enroll a total of 12 patients, and is designed for people afflicted with the common autosomal recessive (AR) form of RP in which both alleles are affected.

Another study showing promise for the AR form of RP is in Phase I trials. It too uses the AAV2 technique. The treatment consists of a corrective MERTK gene, which is delivered to retinal pigment epithelial (RPE) cells by an AAV.4

Related: What the COVID-19 relief package means for ODs

Allergan, in conjunction with Gensight, is undergoing Phase I/II using its GS030 therapy, Optogenetics in which a light-sensing gene therapy is inserted to enhance visual stimulation. The system is designed to restore vision for people who are blind from RP and potentially other retinal conditions, such as Usher syndrome, Stargardt disease, and dry age-related macular degeneration (AMD).10

Using the simple AAV technique, scientists at Berkley have inserted the green opsin photopigment into the genome of ganglion cells in mice. In total, 90 percent of the ganglion cells became sensitive to green light. The mice were able to detect motion, see brightness changes over 1,000-fold range, and even see detail on iPads, equivalent to humans being able to see letters.10

The researchers claim that within several years, humans may be given the ability to read and watch video after retinal degeneration.10

Related: How ODs are addressing COVID-19 in their practices

Stargardt disease
The most common macular dystrophy, defined by lipofuscin accumulation and macular atrophy, is autosomal recessive Stargardt disease. A current clinical trial is using subretinal injection of a lentiviral vector that was shown to express the ABCA4 gene in a mouse model. The rationale for the trial is based on the success of this strategy in reducing lipofuscin in animal models.11

Sanofi is conducting Phase II studies using the lentovirus to resupply the macular cells the corrected gene. In a preclinical model of Stargardt disease, a single administration was effective for the whole of the six-month study.11

Related: Optometry’s year can give ODs an edge with treatments

Best disease
Also known as vitelliform dystrophy, Best disease is caused by mutations in the BEST1 gene and often manifests in children and young adults. BEST1 encodes a transmembrane protein associated with part of the RPE. In Best disease, the RPE unzips its connection with the photoreceptors. Mutations in BEST1 cause detachment of the retina and degeneration of photoreceptor cells.

Scientists in the U.S. say human trials of gene therapy for this disease could be less than two years away, following successful use of the treatment in a canine model of the disease.12

Disease reversal was first apparent in the injected eyes at four weeks post-injection, and treated dogs’ eyes remained free of disease for up to five years. The gene therapy was effective in dogs whether they were treated using the human or the canine BEST1 gene. The technique used was AAV vectoring.12

Related: Unconventional clinical options for lowering IOP

Wet macular degeneration
With gene therapy, wet AMD patients may be able to avoid monthly anti-vascular endothelial growth factor (VEGF) injections. Scientists at the Center for Genome Engineering, within the Institute for Basic Science (IBS), report the use of CRISPR-Cas9 in performing “gene surgery” in the layer of tissue that supports the retina of living mice.13 By editing the VEGF gene, a longer-term cure than anti-VEGF injections can be achieved.

Scientists have developed a treatment to suppress choroidal neovascularization (CNV) by inactivating the VEGF gene using CRISPR-Cas9.6

In a Phase I clinical trial, a gene therapy called Retinostat delivered by injection under the retina has proven safe. The gene continues to make the proper proteins for at least one year after injection, which uses the AAV vectoring technique.14

Related: Retinal detachment seals itself

Treatment without injections
Patients and practitioners alike would rejoice if present therapies as well as future gene therapies could be delivered without the use of injections. The problem, of course, is that most therapeutic gene therapy administered in an alternative manner would be eliminated because of tear dilution and rinsing. The corneal epithelium is almost impermeable to hydrophilic macromolecules.15

However, researchers are working on a solution. The ability to administer anti-VEGF therapies via eye drops is a possibility. The University of Birmingham in the UK is partnering with U.S. company Macregen to deliver this technology. One molecule that has shown great potential to penetrate the cornea and deliver drug to the retina is Penetratin.15

Related: OCT in DR follow-up highlights importance of retina-vitreous attachment

Optometry’s role today
The role of the OD has accelerated over the last few decades. The responsibility in how ODs manage certain patients has now changed forever. Any patient with an IRD should be referred for at the very least genetic profiling and approved FDA treatment in the case of LCA patients. Patients may qualify for ongoing studies if treatment is not approved.

Two resources for referring patients:
The Center for Genetic Eye Diseases, Cole Eye Institute Cleveland Clinic Foundation www.isgedr.com
The Genetic Testing Registry: https://www.ncbi. nlm.nih.gov/gtr/

OD should speak to their patients to explain there is hope and offer basic genetic counseling. As more mainstream genetic therapy treatments become available for diseases such as AMD, glaucoma, it may soon be the standard of care in optometry.

Related: Understanding genetic testing for hereditary disease


1. Chial H. DNA sequencing technologies key to the Human Genome Project. Nature Education. 2008;1(1):219.
2. Taylor P. Spark Therapeutics’ Luxturna advisory committee vote sets gene therapy landmark. FierceBiotech. Available at: https://www.fiercebiotech.com/biotech/spark-therapeutics-luxturna-adcomm-vote-sets-gene-therapy-landmark. Accessed 4/1/20.
3. Kirkendoll SM. Gene Therapy Treatment Targets Rare Mutation Tied to Blindness. Michigan Health Lab. Available at: https://labblog.uofmhealth.org/health-tech/gene-therapy-treatment-targets-rare-mutation-tied-to-blindness. Accessed 4/1/20.
4. Wright AF. Gene therapy for the eye. Br J Ophthalmol. 1997 Aug;81(8):620-3.
5. Hastie E, Samulski RJ. Adeno-associated virus at 50: a golden anniversary of discovery, research, and gene therapy success-a personal perspective. Hum Gene Ther. 2015 May;26(5):257-265.
6. Cabral T, DiCarlo JE, Justus S, Sengillo JD, Xu Y, Tsang SH. CRISPR Applications in Ophthalmologic Genome Surgery. Curr Opin Ophthalmol. 2017 May;28(3):252-259.
7. National Institutes of Health. Use of Genetically Modified Stem Cells in Experimental Gene Therapies. Available at: https://stemcells.nih.gov/info/2001report/chapter11.htm. Accessed 4/1/20.
8. MacLaren RE, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Seymour L, Clark KR, During MJ, Cremers FP, Black GC, Lotery AJ, Downes SM, Webster AR, Seabra MC.  Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet. 2014 Mar 29;383(9923):1129-37.
9. Yeste J, García-Ramírez M, Illa X, Guimerà A, Hernández C, Simó R, Villa R. A compartmentalized microfluidic chip with crisscross microgrooves and electrophysiological electrodes for modeling the blood-retinal barrier. Lab Chip. 2017 Dec 19;18(1):95-105.
10. Sanders R. With single gene insertion, blind mice regain sight. Berkeley News. Available at: https://news.berkeley.edu/2019/03/15/with-single-gene-insertion-blind-mice-regain-sight/. Accessed 4/1/20.
11. Kong J, Kim SR, Binley K, Pata I, Doi K, Mannik J, Zernant-Rajang J, Kan O, Iqball S, Naylor S, Sparrow JR, Gouras P, Allikmets R. Correction of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene therapy. Gene Ther. 2008 Oct;15(19):1311-1320.
12. Guziewicz KE, Cideciyan A, Beltran WA, Komáromy AM, Dufour VL, Swider M, Iwabe S, Sumaroka A, Kendrick BT, Ruthel G, Chiodo VA, Héon E, Hauswirth WW, Jacobson SG, Aguirre GD. BEST1 gene therapy corrects a diffuse retina-wide microdetachment modulated by light exposure. Proc Natl Acad Sci U S A. 2018 Mar 20;115(12):E2839-E2848.
13. Kim K, Park SW, Kim JH, Lee SH, Kim D, Koo T, Kim KE, Kim JH, Kim JS. Genome surgery using Cas9 ribonucleoproteins for the treatment of age-related macular degeneration. Genome Res. 2017 Mar;27(3):419-426.
14. Clinicaltrials.gov. Phase I Dose Escalation Safety Study of RetinoStat in Advanced Age-Related Macular Degeneration (AMD) (GEM). Available at: clinicaltrials.gov/ct2/show/NCT01301443. Accessed 4/1/20.
15. de Cogan F, Hill LJ, Lynch A, Morgan-Warren PJ, Lechner J, Berwick MR, Peacock AFA, Chen M, Scott RAH, Xu H, Logan A. Topical Delivery of Anti-VEGF Drugs to the Ocular Posterior Segment Using Cell-Penetrating Peptides. Invest Ophthalmol Vis Sci. 2017 May 1;58(5):2578-2590.

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