Intravitreal gene therapy

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Intravitreal gene therapy represents an approach to treating retinal diseases by delivering therapeutic genes directly into the vitreous humor of the eye. [1] This method uses a viral vector, often an adeno-associated virus (AAV), to carry genetic material into retinal cells. Once inside, the therapeutic genes are expressed to address genetic deficiencies or modify biological pathways, offering a long-term or potentially permanent treatment ("biofactory approach") for conditions like wet age-related macular degeneration (AMD), diabetic macular edema, and inherited retinal dystrophies. [2] Unlike traditional therapies requiring frequent injections, intravitreal gene therapy aims to reduce the treatment burden while improving efficacy potentially providing lifelong benefit.

Contents

Advantages and Challenges

One of the key advantages of intravitreal administration is its minimally invasive nature compared to subretinal delivery. [3] Intravitreal injections are already commonly used for administering drugs like anti-VEGF agents, making the procedure familiar to clinicians and safer for patients. The eye's immune-privileged status reduces the likelihood of immune responses to the viral vector, increasing the therapy's safety profile. Emerging clinical trials are exploring this modality's potential, with promising results indicating sustained benefits over months or years after a single treatment.

Despite its potential, challenges remain. One major hurdle is ensuring efficient transduction of retinal cells via the intravitreal route, as the viral vectors must traverse physical and biological barriers. Additionally, safety concerns, such as inflammation or unintended effects on neighboring cells, must be carefully monitored. Ongoing innovations in vector design and delivery systems aim to address these issues, paving the way for broader applications of intravitreal gene therapy in ophthalmology. This field continues to evolve, offering hope for more effective and less invasive treatments for debilitating eye diseases.

Investigational agents

Investigational agents for intravitreal and subretinal gene therapies are advancing rapidly, targeting various retinal disorders. In neovascular age-related macular degeneration (nAMD), key intravitreal agents include Adverum Biotechnologies’ ixoberogene soroparvovec (ixo-vec) and 4D Molecular Therapeutics’ 4D-150. [4] Both use innovative mechanisms to produce anti-VEGF proteins directly within the eye, significantly reducing the need for frequent anti-VEGF injections. Janssen’s JNJ-1887 targets dry AMD with a complement pathway approach, while other agents like RGX-314 from REGENXBIO focus on sustained anti-VEGF effects delivered via subretinal routes. [5] [6] These therapies demonstrate promising improvements in retinal structure and vision while minimizing treatment burdens.

For inherited retinal diseases, several subretinal therapies are in advanced stages. [7] MeiraGTx's botaretigene sparoparvovec targets X-linked retinitis pigmentosa through RPGR gene restoration and Beacon Therapeutics’ laruparetigene zosaparvovec aims at similar conditions, showing retinal sensitivity improvements in trials. [8] Another notable effort is Atsena Therapeutics’ ATSN-201 for X-linked retinoschisis. [9] These therapies focus on gene replacement to preserve or restore vision. However, challenges such as delivery complexities and immunogenicity remain.

Future directions include improving delivery techniques like suprachoroidal catheter systems, which avoid invasive procedures, and addressing scalability and cost concerns. [10] The goal is to transform these therapies into accessible options, providing lasting benefits and potentially revolutionizing care for both common and rare retinal disorders .

Related Research Articles

The National Eye Institute (NEI) is part of the U.S. National Institutes of Health (NIH), an agency of the U.S. Department of Health and Human Services. The mission of NEI is "to eliminate vision loss and improve quality of life through vision research." NEI consists of two major branches for research: an extramural branch that funds studies outside NIH and an intramural branch that funds research on the NIH campus in Bethesda, Maryland. Most of the NEI budget funds extramural research.

<span class="mw-page-title-main">Macular edema</span> Medical condition

Macular edema occurs when fluid and protein deposits collect on or under the macula of the eye and causes it to thicken and swell (edema). The swelling may distort a person's central vision, because the macula holds tightly packed cones that provide sharp, clear, central vision to enable a person to see detail, form, and color that is directly in the centre of the field of view.

<span class="mw-page-title-main">Macular degeneration</span> Vision loss due to damage to the macula of the eye

Macular degeneration, also known as age-related macular degeneration, is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, some people experience a gradual worsening of vision that may affect one or both eyes. While it does not result in complete blindness, loss of central vision can make it hard to recognize faces, drive, read, or perform other activities of daily life. Visual hallucinations may also occur.

<span class="mw-page-title-main">Intravitreal administration</span>

Intravitreal administration is a route of administration of a drug, or other substance, in which the substance is delivered into the vitreous humor of the eye. "Intravitreal" literally means "inside an eye". Intravitreal injections were first introduced in 1911 when Ohm gave an injection of air into the vitreous humor to repair a detached retina. In the mid-1940s, intravitreal injections became a standard way to administer drugs to treat endophthalmitis and cytomegalovirus retinitis.

<span class="mw-page-title-main">Presumed ocular histoplasmosis syndrome</span> Medical condition

Presumed ocular histoplasmosis syndrome (POHS) is a syndrome affecting the eye, which is characterized by peripheral atrophic chorioretinal scars, atrophy or scarring adjacent to the optic disc and maculopathy.

<span class="mw-page-title-main">Pegaptanib</span> Drug to treat macular degeneration

Pegaptanib sodium injection is an anti-angiogenic medicine for the treatment of neovascular (wet) age-related macular degeneration (AMD). It was discovered by NeXstar Pharmaceuticals and licensed in 2000 to EyeTech Pharmaceuticals, now OSI Pharmaceuticals, for late stage development and marketing in the United States. Gilead Sciences continues to receive royalties from the drugs licensing. Outside the US pegaptanib is marketed by Pfizer. Approval was granted by the U.S. Food and Drug Administration (FDA) in December 2004.

<span class="mw-page-title-main">Choroidal neovascularization</span> Creation of new blood vessels in the choroid layer of the eye

Choroidal neovascularization (CNV) is the creation of new blood vessels in the choroid layer of the eye. Choroidal neovascularization is a common cause of neovascular degenerative maculopathy commonly exacerbated by extreme myopia, malignant myopic degeneration, or age-related developments.

<span class="mw-page-title-main">Intraocular hemorrhage</span> Medical condition

Intraocular hemorrhage is bleeding inside the eye. Bleeding can occur from any structure of the eye where there is vasculature or blood flow, including the anterior chamber, vitreous cavity, retina, choroid, suprachoroidal space, or optic disc.

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

Joan Whitten Miller is a Canadian-American ophthalmologist and scientist who has made notable contributions to the treatment and understanding of eye disorders. She is credited for developing photodynamic therapy (PDT) with verteporfin (Visudyne), the first pharmacologic therapy for retinal disease. She also co-discovered the role of vascular endothelial growth factor (VEGF) in eye disease and demonstrated the therapeutic potential of VEGF inhibitors, forming the scientific basis of anti-VEGF therapy for age-related macular degeneration (AMD), diabetic retinopathy, and related conditions.

Anti–vascular endothelial growth factor therapy, also known as anti-VEGF therapy or medication, is the use of medications that block vascular endothelial growth factor. This is done in the treatment of certain cancers and in age-related macular degeneration. They can involve monoclonal antibodies such as bevacizumab, antibody derivatives such as ranibizumab (Lucentis), or orally-available small molecules that inhibit the tyrosine kinases stimulated by VEGF: sunitinib, sorafenib, axitinib, and pazopanib.

Geographic atrophy (GA), also known as atrophic age-related macular degeneration (AMD) or advanced dry AMD, is an advanced form of age-related macular degeneration that can result in the progressive and irreversible loss of retinal tissue (photoreceptors, retinal pigment epithelium, choriocapillaris) which can lead to a loss of visual function over time. It is estimated that GA affects over 5 million people worldwide and approximately 1 million patients in the US, which is similar to the prevalence of neovascular (wet) AMD, the other advanced form of the disease.

Elizabeth P. Rakoczy is a Hungarian-born molecular ophthalmologist. She is a professor at the University of Western Australia. She started the molecular ophthalmology department at the Lions Eye Institute. In 2017, Rakoczy was awarded the Florey Medal for her human gene therapy trial to modify viruses for the treatment of wet age-related macular degeneration.

<span class="mw-page-title-main">Faricimab</span> Medication for macular degeneration

Faricimab, sold under the brand name Vabysmo, is a monoclonal antibody used for the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME). Faricimab is the first bispecific monoclonal antibody to target both vascular endothelial growth factor (VEGF) and angiopoietin 2 (Ang-2). By targeting these pathways, faricimab stabilizes blood vessels in the retina. It is given by intravitreal injection by an ophthalmologist.

<span class="mw-page-title-main">Paul A. Sieving</span>

Paul A. Sieving is a former director of the National Eye Institute, part of the U.S. National Institutes of Health. Prior to joining the NIH in 2001, he served on the faculty of the University of Michigan Medical School as the Paul R. Lichter Professor of Ophthalmic Genetics. He also was the founding director of the Center for Retinal and Macular Degeneration in the university's Department of Ophthalmology and Visual Sciences. 

<span class="mw-page-title-main">Intravitreal injection</span> Method of administration of drugs into the eye by injection with a fine needle

Intravitreal injection is the method of administration of drugs into the eye by injection with a fine needle. The medication will be directly applied into the vitreous humor. It is used to treat various eye diseases, such as age-related macular degeneration (AMD), diabetic retinopathy, and infections inside the eye such as endophthalmitis. As compared to topical administration, this method is beneficial for a more localized delivery of medications to the targeted site, as the needle can directly pass through the anatomical eye barrier and dynamic barrier. It could also minimize adverse drug effects on other body tissues via the systemic circulation, which could be a possible risk for intravenous injection of medications. Although there are risks of infections or other complications, with suitable precautions throughout the injection process, chances for these complications could be lowered.

Conbercept, sold under the commercial name Lumitin, is a novel vascular endothelial growth factor (VEGF) inhibitor used to treat neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME). The anti-VEGF was approved for the treatment of neovascular AMD by the China State FDA (CFDA) in December 2013. As of December 2020, conbercept is undergoing phase III clinical trials through the U.S. Food and Drug Administration’s PANDA-1 and PANDA-2 development programs.

<span class="mw-page-title-main">Stem cell therapy for macular degeneration</span> Use of stem cells to treat macular degeneration

Stem cell therapy for macular degeneration is an emerging treatment approach aimed at restoring vision in individuals suffering from various forms of macular degeneration, particularly age-related macular degeneration (AMD). This therapy involves the transplantation of stem cells into the retina to replace damaged or lost retinal pigment epithelium (RPE) and photoreceptor cells, which are critical for central vision. Clinical trials have shown promise in stabilizing or improving visual function, but are nevertheless inefficient.

Polypoidal choroidal vasculopathy (PCV) is an eye disease primarily affecting the choroid. It may cause sudden blurring of vision or a scotoma in the central field of vision. Since Indocyanine green angiography gives better imaging of choroidal structures, it is more preferred in diagnosing PCV. Treatment options of PCV include careful observation, photodynamic therapy, thermal laser, intravitreal injection of anti-VEGF therapy, or combination therapy.

Ixoberogene soroparvovec, is a gene therapy developed by Adverum Biotechnologies for wet age-related macular degeneration. It is delivered via the viral vector AAV.7m8.

References

  1. ↑ "Retina Society 2024: Advances in AMD therapy highlight different mechanisms of action with a common goal". Ophthalmology Times. 2024-09-15. Retrieved 2024-11-24.
  2. ↑ "Retinal Physician Special Edition 2020: The Eye As A Biofactory". digital.retinalphysician.comhttps. Retrieved 2024-11-28.
  3. ↑ Ross, Maya; Ofri, Ron (2021). "The future of retinal gene therapy: evolving from subretinal to intravitreal vector delivery". Neural Regeneration Research. 16 (9): 1751–1759. doi: 10.4103/1673-5374.306063 . ISSN   1673-5374. PMC   8328774 . PMID   33510064.
  4. ↑ Khanani, Arshad M.; Boyer, David S.; Wykoff, Charles C.; Regillo, Carl D.; Busbee, Brandon G.; Pieramici, Dante; Danzig, Carl J.; Joondeph, Brian C.; Major, James C.; Turpcu, Adam; Kiss, Szilárd (2024). "Safety and efficacy of ixoberogene soroparvovec in neovascular age-related macular degeneration in the United States (OPTIC): a prospective, two-year, multicentre phase 1 study". Lancet eClinicalMedicine. 67: 102394. doi:10.1016/j.eclinm.2023.102394. PMC   10751837 . PMID   38152412.
  5. ↑ Campochiaro, Peter A; Avery, Robert; Brown, David M; Heier, Jeffrey S; Ho, Allen C; Huddleston, Stephen M; Jaffe, Glenn J; Khanani, Arshad M; Pakola, Stephen; Pieramici, Dante J; Wykoff, Charles C; Van Everen, Sherri (2024). "Gene therapy for neovascular age-related macular degeneration by subretinal delivery of RGX-314: a phase 1/2a dose-escalation study". The Lancet. 403 (10436): 1563–1573. doi:10.1016/S0140-6736(24)00310-6.
  6. ↑ "RGX-314 Gene Therapy Trial Shows Promise in Treating Wet Macular Degeneration". www.houstonmethodist.org. Retrieved 2024-11-24.
  7. ↑ Georgiou, Michalis; Fujinami, Kaoru; Michaelides, Michel (2021). "Inherited retinal diseases: Therapeutics, clinical trials and end points—A review". Clinical & Experimental Ophthalmology. 49 (3): 270–288. doi:10.1111/ceo.13917. ISSN   1442-6404.
  8. ↑ Michaelides, Michel; Besirli, Cagri G.; Yang, Yesa; De Guimaraes, Thales A.C.; Wong, Sui Chien; Huckfeldt, Rachel M.; Comander, Jason I.; Sahel, José-Alain; Shah, Syed Mahmood; Tee, James J.L.; Kumaran, Neruban; Georgiadis, Anastasios; Minnick, Pansy; Zeldin, Robert; Naylor, Stuart (2024). "Phase 1/2 AAV5-hRKp.RPGR (Botaretigene Sparoparvovec) Gene Therapy: Safety and Efficacy in RPGR-Associated X-Linked Retinitis Pigmentosa". American Journal of Ophthalmology. 267: 122–134. doi:10.1016/j.ajo.2024.05.034.
  9. ↑ "Christine N. Kay, MD: Interim Data on ATSN-201 Shows Promise for XLRS". HCP Live. 2024-10-23. Retrieved 2024-11-25.
  10. ↑ Felder, Anthony E.; Leiderman, Yannek I.; Tomback, Matthew; Chicano, Aaron; Burek, Manuela; Arendovich, Xenon; Wilkens, Kimberlee; Frisbie, Charles; Luciano, Cristian; Kanu, Levi N.; Pfanner, Peter (2020-11-16). "Design of a navigational catheter system for the targeted delivery of therapeutics within the suprachoroidal space". Journal of Medical Engineering & Technology. 44 (8): 508–516. doi:10.1080/03091902.2020.1831632. ISSN   0309-1902. PMID   33118388.
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