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Gene Therapy Advances in Age-Related Macular Degeneration

Tufts University
An illustration of a syringe on a colorful background of DNA molecules
Learn about ongoing research and the future potential for using gene therapy to treat wet and dry age-related macular degeneration.

During the previous twenty years, several drugs have become available that can treat the wet form of age-related macular degeneration (AMD). However, for a large number of patients, these drugs are not as effective as originally hoped, in large part because patients are not compliant with the frequency of intraocular injections (every four to six weeks) necessary for these drugs to be effective. Thus, there is a need for the development of a drug for the treatment of AMD that does not need to be injected repeatedly, ideally, just once.

How Can Gene Therapy be Applied in Wet AMD?

In the case of wet AMD, new blood vessels grow from the back of the eye (choroid) into an area known as the subretinal space. Drugs such as Lucentis® (ranibizumab; an antibody fragment) or Eylea® (aflibercept; a recombinant protein) block the activity of vascular endothelial growth factor (VEGF), a protein essential for the growth of new blood vessels in the eye.

What if instead of an injection of these drugs, one could use the eye itself to locally produce the drug? This can be achieved through the application of gene therapy, whereby cells in the eye are infected with a virus called adeno-associated virus (AAV) that delivers the code (DNA) for making the drug. Once the virus is inside the cells, the code is used by the cells to produce the drug indefinitely.

AAV does not cause any diseases in humans and is thus regarded by the FDA as a relatively safe virus for use in ocular gene therapy. A single intraocular injection of AAV could theoretically produce the drug locally in the eye for the lifetime of a person with AMD. This is a highly attractive proposition for patients that wish to avoid frequent intraocular injections.

Ongoing Wet AMD Gene Therapy Clinical Trials

As for any drug, gene therapy clinical trials need to be conducted in three Phases: I, II, and III. Phase I is generally conducted to test the safety of a novel drug, and phases II and III test the efficacy of such drugs.

There are currently two gene therapy clinical trials ongoing for the wet form of AMD and both have been found to be safe. One of them is an AAV containing the code for Eylea (ADVM-022), and this clinical trial (OPTIC) is being conducted by Adverum Biotechnologies.

Another similar clinical trial is being conducted by RegenxBio using a virus called RGX-314, and this trial is also at the stage of Phase I. RGX-314 is an AAV containing the code for an anti-VEGF antibody fragment.

What about Dry AMD?

There is currently one gene therapy clinical trial ongoing for the dry form of AMD. This trial is being conducted by Hemera Biosciences and is using an AAV (HMR59) to target a part of the immune system known as complement. The end stage of activation of complement results in the formation of the membrane attack complex (MAC) in the eye, and MAC has been found to be elevated in the eyes of dry AMD patients. Inhibition of MAC using a protein known as CD59 (protectin) may potentially reduce the advancement of dry AMD. HMR59 is an AAV containing the code for CD59, and it too has been found to be safe in a Phase I clinical trial for dry AMD.

Future Perspectives

ADVM-022 is injected intravitreally into the eye, whereas RGX-314 is injected subretinally. Whereas intravitreal injections are a standard and routine office procedure, subretinal injections require surgery and have significant risks of damage to the retina. Thus, if the intravitreal approach of Adverum Biotechnologies is effective, it is likely to be the approach preferred by patients.

On the other hand, intravitreal injections are generally more immunogenic and do not deliver the DNA deep into the retina, the location of the new blood vessels involved in macular degeneration. Adverum Biotechnologies is utilizing a novel retinal-penetrating AAV to address these technical limitations.

Recently, a novel approach of AAV delivery to the eye has been developed known as suprachoroidal injection. Suprachoroidal injections are likely much safer than subretinal injections, and RegenxBio has recently initiated a clinical trial (AAVIATE) using this novel approach for delivery of RGX-314 for wet AMD; the first patient having been injected in September 2020.

In addition to the clinical trials discussed above, a very large number of preclinical studies show significant promise for the treatment of AMD. While it is too early to know whether any of these approaches will be effective in the treatment of AMD, the field is rapidly evolving and is very likely poised to make a big impact in the lives of people with AMD in the future.


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This content was first posted on: September 30, 2020

The information provided here is a public service of the BrightFocus Foundation and should not in any way substitute for personalized advice of a qualified healthcare professional; it is not intended to constitute medical advice. Please consult your physician for personalized medical advice. BrightFocus Foundation does not endorse any medical product, therapy, or resources mentioned or listed in this article. All medications and supplements should only be taken under medical supervision. Also, although we make every effort to keep the medical information on our website updated, we cannot guarantee that the posted information reflects the most up-to-date research.

These articles do not imply an endorsement of BrightFocus by the author or their institution, nor do they imply an endorsement of the institution or author by BrightFocus.

Some of the content may be adapted from other sources, which will be clearly identified within the article.

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