From Bionic Eye to Gene Therapy: Is futuristic technology the way forward in the fight against retinal dystrophy?

How do you beat something that is not only degenerative but also possesses the superpowers of clinical and genetic heterogeneity? Retinal dystrophies (RDs) are the leading cause of hereditary blindness with the following common presentations: color blindness or night blindness, peripheral vision abnormalities, and subsequent progression to complete blindness in progressive conditions.

In a special session yesterday at the RANZCO 52nd Annual Scientific Congress, experts shared tips on how to diagnose and treat this group of degenerative and hereditary retinal disorders.

Make a Thorough Genetic Diagnosis

To date, some 280 genes are known to be associated with different phenotypes of RDs. Mutations within the same gene have been associated with different phenotypes, even within different individuals of the same family

According to Assoc. Prof. Andrea Vincent from the University of Auckland, New Zealand, clinical phenotyping in inherited retinal disease can be used to guide clinicians in making a genetic diagnosis.

“It starts with history. Find commonality — a clinical examination — obviously not only of the patient, but they usually have one or two family members in the room, and examine them. Then we have a host of tools that we can use, optical coherence tomography (OCT), widefield imaging and fundus autofluorescence, my favorite mode ever,” shared Assoc. Prof. Vincent.

“Once we have every little slice (of information), we can try and put them together to come up with a diagnosis,” she added.

She noted that signs and symptoms could be determined by observing how the patient behaves in different lighting conditions, whether they are light-sensitive or unhappy when the lights are turned off at night.

“The genetics of the inherited disease is complex, but by really honing in on our clinical phenotyping and getting a good pedigree, clinical phenotyping will inform genotyping and subsequently help us coordinate in genetic environments,” she said.

Embrace the Challenges and Limitations of Gene Therapy

While ophthalmology is at the forefront of the fast-moving field of gene therapy, limitations and challenges remain.

“The treatments are very expensive, and they’re limited to a relatively small number of our patients at this stage,” said Dr. Thomas Edwards, vitreoretinal surgeon and head of Retinal Gene Therapy Research at the Centre for Eye Research Australia, who presented the potential of gene therapy for inherited retinal disease.

“With that said, it’s a very fast-paced field and the Food and Drug Administration (FDA) is predicting 10 to 20 new gene therapies approved per year by 2025,” he added.

Financing in the regenerative medicine sector is also seeing an exponential rise — from US$6 billion in 2019 up to US$20 billion in 2020.

The range of potential objectives is to restore the function of a gene, silence the aberrant function of a gene, induce a new function or manipulate a known disease pathway, or induce a neuroprotective effect.

Gene therapy strategies include gene replacement or augmentation, genome editing, optogenetics and RNA modulation.

In gene replacement or augmentation, a working copy of the gene is delivered to affected cells. “Using CRISPR/Cas9-related techniques to edit the patient’s own DNA is a good strategy for when you’ve got, for example, a missense mutation, which causes a dominant-negative or toxic kind of function, mutation,” Dr. Edwards explained.

In a clinical trial phase for LCA10 (CEP290), Leber congenital amaurosis type 10 (LCA10), an autosomal recessive disorder caused by a mutation that causes an exon to form in an area of intronic DNA that should not be there, which causes premature truncation of the gene.

Optogenetics is for advanced disease, where perhaps the patient has lost all of their photoreceptors. There are clinical trials ongoing for these optogenetics approaches, with their own challenges. However, for someone who may have next to no vision, this new technology may prove to be exciting.

Another approach is using RNA and small RNA molecules to knock down disease-causing messenger RNAs, alter their pattern of splicing or block translation.

“Inherited retinal diseases generally progress very slowly. So the challenge now is really to develop novel outcome measures that can control a treatment effect early, early on,” Dr. Edwards said.

From Bionic Eye to Gene Therapy: Is futuristic technology the way forward in the fight against retinal dystrophy?

Bionic Eye and Other Innovations to the Rescue!

Assoc. Prof. Penny Allen, vitreoretinal surgeon and head of the Vitreoretinal Unit at The Royal Victorian Eye and Ear Hospital in Australia, provided updates on a futuristic bionic eye that can partially restore sight loss due to retinitis pigmentosa (RP), an umbrella term for many inherited retinal diseases.

A bionic eye is a revolutionary device that can use electrical or light energy to stimulate visual impulses in patients who are otherwise severely visually impaired.

It comprises an imager or camera that converts light into an electrical signal, electronics to process the image and generate electrical stimulus pulses, and microelectrodes to stimulate the retina.

“Despite the absence of photoreceptors, there is a largely intact neural retina. It is the presence of this intact neural retina that can be stimulated by a device within the eye and offers the opportunity for vision,” said Assoc. Prof. Allen, who is also the head of the Bionic Eye Research team at the Centre for Eye Research Australia.

Previously, there were three commercially-available devices, but all three have now been suspended.

A six-month safety and efficacy trial of the Intelligent Reti Implant System II Device in RP saw 10 participants successfully implanted. There were six serious adverse events in four patients, including leg phlebitis, hypotony and persistent ocular pain.

All results were better with the device on compared to the device off.

The limitations of all devices include low resolution, surgical difficulty and complications which vary between the approaches. The proximity to target neurons also varies.

Retinal prostheses do offer the possibility of navigational and object localization for profoundly blind patients. However, image fading is a real issue, and multidisciplinary teams are required to solve the issues associated with these devices.

There are also other cortical devices with the aim of treating patients with visual loss due to other causes than retinal dystrophy.

Second Sight’s Orion Visual Cortical Prosthesis System (Orion), an implanted cortical stimulation device, is intended to provide useful artificial vision to individuals who are blind due to a wide range of causes, including glaucoma, diabetic retinopathy, optic nerve injury or disease and eye injury.

It aims to convert images captured by a miniature video camera mounted on glasses into a series of small electrical pulses. A six-subject early feasibility study of the Orion is currently underway, with the first patient implanted in 2018. There are no published results as of yet.

Editor’s Note: A version of this article was first published in Issue 3 of CAKE & PIE POST (52nd RANZCO Brisbane 2022 Edition). The 52nd Annual Scientific Congress of The Royal Australian and New Zealand College of Ophthalmologists (RANZCO Brisbane 2022) was held virtually from February 26 to March 1. Reporting for this story took place during the event.

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