Gene Therapy For Blindness

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Overview

When a car’s engine begins to malfunction or show defects, we take it to an automobile mechanic who will either repair or replace the faulty component to ensure the engine runs smoothly again. Similarly, genetic defects in human beings can be corrected using a technique known as human gene therapy (HGT)

Wondering how that is possible? Human gene therapy works by transferring genetic materials encoded within nucleic acids (DNA) to a patient’s somatic cells to bring about therapeutic effects by reversing the genetic defects or sometimes through the overexpression of nucleic acids that can overshadow the disease.1

The applications of gene therapy can be vast and multi-dimensional. It has been proven to be useful in treating diseases such as Parkinson’s, haemophilia, Alzheimer’s, brain tumours, sickle cell diseases, blindness and so on. The amazing news is that this list goes on and on and is only predicted to grow with the exponential advancement gene therapy has seen in the past few years. 

There has been a growing interest in the applications of gene therapy in treating blindness and we have seen an enormous advancement in this technology to treat different types of eye-related diseases. Gene therapy has already found its way into spearheading the reversal of inherited retinal diseases (IRDs) that are caused due to either a mutated or faulty gene.2 Gene therapy’s significance in treating other types of vision impairment such as age-related macular degeneration (AMD), corneal eye disease and diabetic macular oedema (DME) is extensively researched. 

Gene therapy can aid in curing blindness by delivering a gene replacement to retinal cells that cannot produce the essential proteins for vision. The first-ever one-time gene therapy to treat IRDs known as Luxturna (containing the active substance voretigene neparvovec-rzyl) was approved by the Food and Drug Administration (FDA) in 2017, which has corrected vision and eliminated blindness for patients.3

Types of blindness targeted by gene therapy

  1. Inherited retinal diseases (IRDs)
    1. Retinitis pigmentosa (RP)
    2. Leber congenital amaurosis (LCA)

IRDs are the only type of blindness for which there is an existing gene therapy mechanism that was approved by the FDA. 

  1. Age-related macular degeneration
  2. Diabetic macular oedema (DME)
  3. Corneal eye disease

Other aforementioned types of blindness can also potentially be cured or reversed using gene therapy. However, it is good to know that gene therapy mechanisms for types of blindness other than IRDs are still in ongoing clinical trials and might still take a long time to become approved and reach the market. 

Mechanisms of gene therapy

Disease-causing gene identification and cloning

The first and foremost step in gene therapy treatments is to identify the diseased or mutated gene that is causing the disease so that an identical healthy gene can be constructed using gene cloning or genetic engineering techniques.4 This newly constructed gene is called the therapeutic gene or transgene scientifically. We can compare this to replacing furniture living room to match the aesthetics of your dream home. The initial step would be to identify the furniture that needs to be replaced so that new pieces can be ordered. 

The transgene is tailor-made to fit the mechanism of action that is planned including gene augmentation, suppression or repair.4 

Introduction of therapeutic genes

The next step is the introduction of therapeutic genes to the disease site, no matter what disease it is targeting. To finally set your dream home with furniture that matches your aesthetics, you first need the furniture parts to be delivered to your place by the furniture store or sometimes through delivery partners like DPD or DHL. 

Delivery partners, scientifically known as vectors, are an essential part of making sure that the gene gets delivered or transported to the accurate site of action, retinal cells in this case. There are two major types of delivery partners that gene therapy entails as follows: 

1. Viral vectors

Lentivirus (LV), adenovirus (Ad), and adeno-associated virus (AAV) are some of the most popular choices of viral vectors in the biological sciences world. You might worry about the idea of a virus being injected into your body to treat another disease but there is nothing to worry about the viral characteristics of the vector. The viral vector’s genetic materials or sequences that encode viral proteins to bring about its typical characteristics are deleted from the vector, making it gutless.5 This ensures that the vector does not exhibit any viral properties nor replicate or mutate within the patient's body. 

The viral vector is then genetically engineered or cloned to express the therapeutic gene using mechanisms such as CRISPR-Cas9, TALEN, and zinc finger nuclease (ZFN). The viral vector encoded only with the gene that has to be delivered to the retina is then locally administered to the retinal cells5. It is either injected into the subretinal space, achieved through a transient detachment of the retina, or into the vitreous cavity using an intravitreal injection mechanism.5

2. Non-viral vectors

Even though viral vectors are excellent at delivering therapeutic genes to the disease site, they have certain limitations due to their immunogenicity and cytotoxicity. Non-viral vectors are less efficient compared to their viral counterparts in transfecting host cells but are easy to produce, have lower pathogenicity and immunotoxicity and have higher safety implications and advantages.4 Due to the drawbacks in its efficacy in the delivery system that affects the transgene expression, more research has to be done to find a non-viral vector that can fulfil all the properties of an ideal vector. Some examples of non-viral vectors include physical methods, needles, microprojectile gene transfer, electroporation, sonoporation, hydroporation and so on.4 

Correction of genetic mutations

The therapeutic genetic material (transgene) is delivered to the nucleus of the target cell by the vector and it binds to receptors on the retinal cells, where it injects the transgenic material. The transgene is then integrated into the DNA in the nucleus, leading to the correction of the defective or mutated gene that is causing blindness.4 This would be the part where you are done assembling your furniture and your dream living room aesthetics come to life. 

Clinical trials and future prospects

Success story

As previously discussed, the FDA-approved Luxturna treating IRDs has been the breakthrough for gene therapy to treat blindness in the scientific world. Luxturna is administered using a viral vector and corrects IRDs by introducing a new gene that replaces the broken or mutated one to improve vision. It is also proven to aid in preventing further vision loss caused by RP and LCA in patients. 

Ongoing research

Other ongoing clinical research is focused on reversing other types of blindness using gene therapy mechanisms.

Age-related macular degeneration (AMD)

Age-related macular degeneration (AMD) has been a main focus of research in this field. AMD affects the patient’s central vision and can end up in severe deterioration of vision. Age and lifestyle factors are some of the major risk factors leading to this disease that can rarely result in total blindness.

The breakthrough new-generation gene therapy to treat AMDs follows a mechanism of action where a gene is introduced that can prompt retinal cells to create a novel therapeutic protein that can reverse the adverse effects of AMD.6 Research has shown promising results and claims the new generation gene therapy’s capability to permanently protect patients with neovascular AMD with the aid of a single injection, which is also proving it to be minimally invasive.6

Some examples of gene therapies to treat AMDs still undergoing clinical trials are RGX-314 by Regenxbio and ADVM-022 by Adverum Biotechnologies directed at treating wet (advanced neovascular) AMD and GT-005 by Gyroscope Therapeutics to treat dry AMD.6,7

Diabetic macular oedema (DME)

DME is a disease that commonly occurs as a microvascular complication of diabetes mellitus and causes visual impairment due to the thickening of the retina resulting from an excessive accumulation of intraretinal fluid in the extracellular space around the retina. Currently, anti-VEGF therapy is the preferred treatment mechanism given to patients with DME. FT-003 is a gene therapy mechanism that is still in phase 1 clinical trials that acts by providing intraocular protein to be expressed in the retinal cells to attain therapeutic effects that can prevent vision loss in patients.8

Corneal eye disease

Corneal disease, including keratitis, corneal dystrophy and corneal ectasia, is one of the leading causes of vision loss globally and is caused by a range of risk factors including genetic mutations and injuries to the eye. Hereditary corneal diseases can be reversed using adeno-associated viral (AAV) vector-mediated gene therapy and this gene therapy mechanism has growing potential due to the accessibility to injections, its immune-privileged characteristics as well as the presence of the blood-retinal barrier that can prevent contamination to other nearby tissues and subsequently to the general blood circulation.9

Limitations and challenges

Just like any breakthrough disease treatment mechanism, gene therapy also, unfortunately, possesses certain limitations, challenges as well as risks that need to be discussed. The major concern is regarding the delivery vehicle itself, which is the vectors being utilised.10 More research has to be done to tailor the vector for the type of disease being targeted and to avoid adverse reactions. 

Moreover, each gene therapy treatment round can only be aimed at fixing one single gene. It is worth noting the fact that retinitis pigmentosa (RP) can be caused due to mutations or faults in 60 different genes, which is a huge scope to be covered and this raises concerns about a timely treatment and the overall cost of it while significantly reducing the number of people who could potentially benefit from each type of gene therapy. 

FAQs

What is gene therapy for blindness?

Gene therapy for blindness involves introducing genetic material into a patient's cells to treat or prevent vision-related disorders. This approach aims to address genetic mutations or deficiencies that contribute to blindness.

What types of blindness can gene therapy address?

Gene therapy is being explored for various types of blindness, including inherited retinal diseases such as retinitis pigmentosa and Leber congenital amaurosis, as well as age-related macular degeneration.

How does gene therapy work for blindness?

Gene therapy for blindness typically involves introducing therapeutic genes into the eye using vectors, such as viral or non-viral delivery systems. These genes may either replace faulty ones or provide additional instructions to correct genetic mutations.

What are the challenges and limitations of gene therapy for blindness?

Challenges include the potential for immune responses, the sustainability of therapeutic effects, and addressing ethical considerations. Accessibility and affordability are also significant concerns, hindering widespread adoption.

Can gene therapy completely restore vision?

The extent of vision restoration depends on the specific condition and the success of the gene therapy. While some patients may experience significant improvement, complete restoration of vision may not be achievable in all cases.

Summary

Gene therapy can aid in curing blindness by delivering a gene replacement to retinal cells that cannot produce the essential proteins for vision. Luxturna’s successful therapeutic effects in treating inherited retinal disorders are indeed opening the door to a promising new world of gene therapy being used to reverse other types of vision impairment. We can stay optimistic with the current scale of clinical trials and research ongoing that the limitations mentioned can be mitigated. 

References

  1. The future of human gene therapy. Molecular Aspects of Medicine [Internet]. 2001 [cited 2024 Jan 12]; 22(3):113–42. Available from: https://www.sciencedirect.com/science/article/abs/pii/S0098299701000048.
  2. Fighting Blindness Canada (FBC) [Internet]. Gene Therapy & Clinical Trials to Treat Vision Loss | Fighting Blindness Canada; [cited 2024 Jan 12]. Available from: https://www.fightingblindness.ca/resources/genetherapy/.
  3. Gao J, Hussain RM, Weng CY. Voretigene Neparvovec in Retinal Diseases: A Review of the Current Clinical Evidence. Clin Ophthalmol [Internet]. 2020 [cited 2024 Jan 12]; 14:3855–69. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671481/.
  4. Ramamoorth M, Narvekar A. Non Viral Vectors in Gene Therapy- An Overview. J Clin Diagn Res [Internet]. 2015 [cited 2024 Jan 12]; 9(1):GE01–6. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347098/.
  5. Dalkara D, Goureau O, Marazova K, Sahel J-A. Let There Be Light: Gene and Cell Therapy for Blindness. Hum Gene Ther [Internet]. 2016 [cited 2024 Jan 12]; 27(2):134–47. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779297/.
  6. Gene Therapy for AMD. American Academy of Ophthalmology [Internet]. 2022 [cited 2024 Jan 12]. Available from: https://www.aao.org/eyenet/article/gene-therapy-for-amd.
  7. Khanani AM, Thomas MJ, Aziz AA, Weng CY, Danzig CJ, Yiu G, et al. Review of gene therapies for age-related macular degeneration. Eye [Internet]. 2022 [cited 2024 Jan 12]; 36(2):303–11. Available from: https://www.nature.com/articles/s41433-021-01842-1.
  8. Frontera Therapeutics. An Open-label, Multy-center, Dose-escalation Clinical Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of FT-003 in Subjects With Diabetic Macular Edema [Internet]. clinicaltrials.gov; 2023 [cited 2024 Jan 1]. Available from: https://clinicaltrials.gov/study/NCT05916391.
  9. Sarkar S, Panikker P, D’Souza S, Shetty R, Mohan RR, Ghosh A. Corneal Regeneration Using Gene Therapy Approaches. Cells [Internet]. 2023 [cited 2024 Jan 12]; 12(9):1280. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10177166/.
  10. Simons EJ, Trapani I. The Opportunities and Challenges of Gene Therapy for Treatment of Inherited Forms of Vision and Hearing Loss. Hum Gene Ther. 2023; 34(17–18):808–20.

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This content is purely informational and isn’t medical guidance. It shouldn’t replace professional medical counsel. Always consult your physician regarding treatment risks and benefits. See our editorial standards for more details.

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Karishma Manoj Kumar

Master of Science - MS, Drug Discovery and Pharma Management, UCL

I am a Drug Discovery and Pharma Management graduate from University College London (UCL) with an entrepreneurial rigour from working in a start-up setting and enthusiasm for life sciences. With previous experience working on diverse projects and internships ranging from life science consulting to public relations and business development, I find life sciences to be a dynamic and rewarding space to feed my ambition and grow holistically while contributing to the healthcare/pharmaceutical value chain.

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