Gene Therapy For Macular Degeneration – The Future of AMD Treatments

Gene therapy for macular degeneration

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Gene therapy has the potential to transform the treatment of a variety of diseases, including macular degeneration. AMD is the most common cause of vision loss in older people, and the current treatment standard is monthly or at least a bimonthly injection, which can be challenging for patients and place a major time and financial burden on them.

Macular Degeneration is a growing problem

Macular degeneration affects an estimated 11 million people in the United States and greater than 190 million people worldwide. The dry type of the disease, which causes irreversible vision loss, affects the vast majority of patients, who are 65 or older. Macular degeneration is expected to affect 22 million Americans by 2050 as the population of the United States becomes older. 

The primary cause of vision loss in the UK is age-related macular degeneration (AMD), which affects over 600,000 people. The disease becomes more common as people become older, with more than 10% of the population over 70 years old displaying indications of AMD. Nearly 700,000 people in the United Kingdom are expected to develop late-stage AMD by 2020. 

Dry AMD is the most prevalent kind of AMD, accounting for roughly 9 out of 10 cases. It occurs when the cells of the macula are destroyed by a build-up of deposits called drusen. It manifests as a gradual and devastating loss of vision in the central visual field (macula). As the disease progresses to the atrophic form (also known as geographic atrophy), which is distinguished by the loss of the retinal pigment epithelium, which leads to degeneration of the surrounding photoreceptor layer, affected patients lose their ability to recognize faces, drive, read, and perform other daily activities. 

The complement system, which is a system of proteins in our immune system that fights germs, is a crucial role in dry AMD. These proteins become overactive in dry AMD and begin to attack the retinal cells in the same way that germs fight bacteria. There are presently no viable treatments for dry AMD, but we have discovered a new gene therapy technology that we hope could help reduce or perhaps stop the progression of the disease. The novel procedure includes implanting copies of a gene that produces GT005, a proprietary protein produced by Gyroscope Therapeutics that helps retinal cells function normally by counteracting the inflammation generated by the complement system. To accomplish so, we’ll need a vector (or carrier) of the normal gene that can safely get the normal genes back into the target retinal cells without causing injury. 

Patients and their families suffer greatly as a result of vision loss, but there are currently no FDA-approved treatments for dry macular degeneration. A treatment that can slow or stop the progressive development of this disease would be extremely beneficial to patients, many of whom live active lives well into their 80s and 90s.

Current macular degeneration treatments

Medications (anti-VEGF medications)

Medications that limit the impact of growth signals sent by the body to develop new blood vessels may assist to stop the growth of new blood vessels. These medications are the first-line treatment for wet macular degeneration at any stage. 

The following medications are used to treat wet macular degeneration: 

  • Brolucizumab (Avastin) Ranibizumab (Lucentis) Aflibercept (Eylea) Bevacizumab (Avastin) Ranibizumab (Lucentis) (Beovu) 
  • These drugs are injected into the afflicted eye by your doctor. To keep the medication’s positive effect, you may need shots every four to six weeks. You may be able to regain some vision when the blood vessels shrink and the fluid behind the retina is absorbed.
  • Conjunctival bleeding, increased eye pressure, infection, retinal detachment, and eye inflammation are all possible side effects of eye injections.
  • The problem with these anti-VEGF medications is that they have to be administered on a monthly basis.  This can be a very big problem for compliance. Many patients are elderly and many have transportation issues.

Gene Therapy Advances in Age-Related Macular Degeneration

Scientists have uncovered a relationship between age-related macular degeneration and variations of complement, an ancient immune system branch. A group of scientists led by Rando Allikmets, Ph.D.,  was one of the first to find that a mutation in a gene that produces the complement protein causes macular degeneration in 2005. Several complement gene variations have now been linked to an increased risk of age-related macular degeneration. 

This trial’s investigational gene therapy (GT005) uses a genetically engineered viral vector to transfer DNA encoding for complement factor I (CFI), a protein that stops the immune system from attacking retinal cells. GT005 is administered as a single surgical injection beneath the retina. 

GT005 is being studied in adults with dry age-related macular degeneration in this clinical investigation. 

Participants in the study will be observed for up to a year to see if the therapy can help reduce the progression of geographic atrophy and to watch for negative effects. 

The FDA has granted GT005 fast-track status for the treatment of geographic atrophy, secondary to dry macular degeneration, which expedites the examination of medications for serious illnesses with no FDA-approved treatment choices.

AAV Vector for gene therapy wet AMD

Several medications to treat the wet form of macular degeneration have become available in the last two decades (AMD). However, these medications are not as helpful as originally intended for a large number of patients, owing in part to patients’ failure to comply with the required frequency of intraocular injections (every four to six weeks). As a result, hence the need for the creation of an AMD treatment medicine that does not require recurrent injections, ideally only once. 

New blood vessels grow from the back of the eye in the case of wet AMD, and a recombinant protein) blocks the activity of vascular endothelial growth factor (VEGF), a protein required for the creation of new blood vessels in the eye. 

What if, instead of injecting these medications into the body, the eye could generate them locally? This can be accomplished through gene therapy, which involves infecting cells in the eye with an adeno-associated virus (AAV) that distributes the drug’s genetic code (DNA). The code is employed by the cells to create the medicine indefinitely once the virus is active inside the cells. 

The vector we utilize is a non-pathogenic little virus known as adeno-associated virus (AAV) (i.e. not known to cause disease). Because AAV is very good at getting into retinal cells, we employed a modified strain of it as the vector for the dry AMD gene therapy. 

The FDA considers AAV to be a reasonably safe virus for use in ocular gene therapy because it does not cause any disorders in humans. A single intraocular injection of AAV might hypothetically manufacture the medicine for the rest of a person’s life in the eye. For patients who want to avoid intraocular injections on a regular basis, this is a very appealing option. 

A vitrectomy is a form of ‘key-hole’ surgery that removes the eye’s transparent internal fluid in order to inject the AAV vector. The treatment is relatively safe, as the body gradually restores the eye’s clear internal jelly in the weeks following surgery. 

Following the vitrectomy, a little amount of fluid containing the AAV vector is injected beneath the retina with a fine needle that is thinner than human hair, resulting in a small fluid-filled blister or bleb beneath the retina. This little area of retinal detachment is only transitory, lasting roughly 24 hours while the fluid is gently absorbed by the retina. This type of surgery usually takes around an hour, and the treatment alone (without the gene therapy) is a common procedure for individuals suffering from retinal detachment.

Positive outcomes for the first phases of the gene therapy for age-related macular degeneration

SDS stands for subretinal delivery system and was created and optimized for precision microinjection into the subretinal area. The Orbit SDS employs a flexible cannula that contours the globe and allows access to the rear of the eye, namely a subretinal region in the posterior section. Without removing the vitreous body or causing a retinotomy, the treatment allows for precision delivery of a specified dosage of infusate to the subretinal area, avoiding potential vitrectomy and retinotomy-related problems. Because the probability of vector suspension outflow into the vitreous body is prevented, inflammation is considerably decreased.   

After the favorable interim results of this first-in-human Phase 1/2 clinical trial, a Phase 2 clinical trial will be conducted to assess the efficacy and safety of the gene therapy in patients with dry macular degeneration who have rare variants in their Complement Factor I (CFI) gene, which is associated with low CFI protein levels in their blood. A similar Phase 2 clinical trial will assess the gene therapy’s safety and efficacy in a larger sample of individuals with dry AMD. 

RGX-314 (Regenxbio), which is administered subretinally or suprachoroidal, and ADVM-022 (Adverum Biotechnologies), which would be delivered intravitreally, are two gene therapy programs in development for AMD. 

The phase 2 AAVIATE trial found that suprachoroidal administration of RGX-314 was safe and effective for AMD. 

Patients in the trial group were more prone to have stable visual acuity and retinal thickness six months following one-time treatment, as well as a 70% reduction in anti-VEGF medication burden. Furthermore, after 6 months, 40% of those in the therapy group were free of anti-VEGF injections. 

In the RGX-314 subretinal studies, several patients had pigmentary abnormalities in their retinas, but no immune-related inflammation was found. 

There was some moderate inflammation in the suprachoroidal trials, which was managed with topical steroids, but there was no chronic inflammation. Because it can be performed in a clinic rather than an operating room, this alternative has the potential to be a game-changer. 

Inflammation has been found in all of the ADVM-022 research groups, which have been treated with oral or topical steroids so far. 

We’ve learned that delivery is crucial in gene therapy. Immune responses differ depending on where it is placed.

Preclinical trials for gene therapy for wet macular degeneration

More gene therapies for AMD treatment are on the horizon, in addition to RGX-314 and ADVM-022, which have reached clinical trials. 

Both RetinoStat (Oxford BioMedica) and AAVCAGsCD59 (Hemera Biosciences), use a recombinant equine infectious anemia virus to prevent the formation of the membrane attack complex, are in phase 1 trials. 

A huge number of preclinical research, in addition to the clinical trials mentioned above, offer substantial promise for the treatment of AMD. While it is too soon to say if any of these approaches will be beneficial in the treatment of AMD, the field is fast growing and is very likely to have a significant impact on the lives of AMD patients in the future.

Conclusion

Anti-VEGF treatment isn’t always effective. At one year, 34.1 percent of the monthly ranibizumab arm and 31.7 percent of the monthly bevacizumab (Avastin) arm in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) showed no significant improvement or worsening of best-corrected visual acuity. 5 While anti-VEGF injections are a significant improvement over earlier alternatives, emerging medicines with higher efficacy or fewer injections would be welcome. 

The pathogenesis of AMD, in contrast to monogenic hereditary retinal illnesses, is assumed to be complex, with various genetic variables and environmental factors contributing to the disease. 

While some genes have been linked to AMD, such as CFH, CFB, and ApoE, our understanding of the disease’s genetic pathophysiology is still lacking. As a result, the American Academy of Ophthalmology suggests that routine genetic testing be avoided.  While the complicated nature of AMD will almost certainly necessitate a multimodal strategy, gene therapy has a strong potential role, as indicated by multiple recent and ongoing trials. 

In Layman’s terms

New gene therapies for macular degeneration are showing promising results in early clinical trials.  These new therapies would help curb the need for ongoing injections of anti-VEGF medications that most patients with wet AMD are currently having to be treated with. The result will be far greater compliance and better visual outcomes.  Some of the therapies may require more invasive one-time procedures and others won’t be so invasive and complicated.  If you are suffering from wet or dry AMD hang in there and keep doing all you can with the current treatments and vitamin regimes, because in the very near future if you maintain your current macular health you will have more and better options.

FAQs for Gene therapy for macular degeneration

FAQ’s

How do you reverse macular degeneration naturally?

Unfortunately there currently isn’t a way to reverse your disease naturally. 

How do you prevent macular degeneration from getting worse?

You can help prevent it from getting worse by taking a good AREDS vitamin, quitting smoking, and eating a healthy diet low in cholesterol and high in green leafy vegetables.

Is there any hope for macular degeneration?

Yes, current clinical trials for gene therapies are looking very promising.

About the Author:
Dr Shaun Larsen

Dr Shaun Larsen

Dr. Shaun Larsen is an optometrist who specializes in low vision services and enhancing vision with contact lenses. He has a passion for making people's lives better by helping them see well enough to read, write, or drive again. He always keeps up with the latest technology so he can help people regain their independence.

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