The results of the international preliminary trials look promising and have sent ripples of excitement across the world of medicine. The BRILLIANCE trial — conducted by an American company, Editas Medicine, for its drug called EDIT-101 at various locations in the US — has shown early success in safety and efficacy of a gene editing drug that is injected under the retina to improve vision.
The 14 volunteers in the phase 1/2 trial suffered from a rare genetic disease called Leber Congenital Amaurosis 10 (LCA), which affects approximately one in 40,000 children in the US. Caused by a mutation in the CEP290 gene, there is no treatment or cure currently for LCA.
The two paediatric patients both reported significant success, while one of the 12 adult volunteers reported drastic improvement in vision.
One of the patients was nine-year-old Jacob Peckham, born with a genetic vision anomaly called retinitis pigmentosa-90, where he could not see distant objects and experienced deteriorating vision. Today, he is social, and able to play sports and video games, Peckham and his parents told CBS News.
The EDIT-101 drug is designed to specifically repair a part of the CEP290 gene called IVS26, which affects a subset of LCA patients, around 1,500 in the US. This drug is an ‘in-vivo genome editing medicine’, meaning that it enters the body, and then starts to edit genes.
This has never been done before. Current gene therapies insert edited genes or cells that have already been edited in the lab. Such therapies are now being adopted worldwide in the field of ocular genomics, including in India.
Gene editing for the eyes
The CRISPR-Cas9 is a new gene editing tool that allows researchers to splice the DNA, cutting it using the equivalent of molecular scissors, and then making modifications, additions, or deletions to the DNA before it gets patched up again. This results in physically altered DNA, which leads to changes in the body’s functions as cells start to perform functions they could not before.
One of the participants in the trial, Olivia Cook, who suffered from LCA, had been experiencing progressive narrowing of her field of vision with the loss of peripheral vision. She also could not see clearly in dim light. Cook participated in the clinical trial in 2019 when she was 17, and saw substantial changes to her vision a few months later.
In the BRILLIANCE trial, a CRISPR machinery was injected under her retina in a quick surgery, which then worked on her DNA inside her eye and led to improved vision.
“Now, post-surgery and post recovery, I am able to see in dimmer lighting with my left eye,” Cook said in an interview with CNN. She added, “My life has mostly changed in terms of being hopeful that there is going to be more science and findings in the future.”
These dramatic improvements again cement CRISPR’s unique usefulness in rapidly advancing gene editing therapies.
However, there already exists another US Food and Drug Administration-approved gene therapy treatment for the eyes, and specifically for LCA. Voretigene neparvovec, sold under the brand name Luxturna by Spark Therapeutics, became the first ever gene therapy medication to be used post approval in the US in 2018.
In contrast to EDIT-101, Luxturna carries a modified and functioning copy of the gene, which is inserted back into the body. This gene then codes for the proteins, which previously did not occur in the body. The new gene copy then starts to improve sight.
This is a form of gene augmentation that can also yield highly productive results for certain mutations.
“Mutations in a gene impact multiple functions, some of which we might not know about. So, it is simply easier and more practical to introduce a normal copy of the required gene that has been edited and augmented in the lab into the body,” explained Dr Indumathi Mariappan, who works on gene therapy for retinal diseases at the LV Prasad Eye Institute in Hyderabad.
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Modified genes
CRISPR is used widely in gene therapies today, where genes are modified before being inserted into the body.
At the LVPEI, Mariappan works on such therapies, where she and her team at the lab produce mutation-free genetically edited cells to insert into the body to treat retinal conditions. She does this using stem cells — specifically pluripotent stem cells, which are raw cells that can grow on to become any other type of cell, such as a skin cell or, in this case, a retinal cell.
Gene therapy, where editing is done ex-vivo or outside the body, instead of in-vivo, also offers other advantages in treating cells that do not regenerate. A prime example is retinal cells, the entirety of which we are born with, and which do not multiply, but eventually age and die.
“In older patients, where total degeneration of cells has occurred, there is nothing that can be manipulated with the DNA because new cells can’t be produced. One of the things we do regularly now is replacing cells that provide the same functional response and restore vision,” said Mariappan, who prefers the less expensive, less tedious and more established ex-vivo procedure, which suits India better.
She also explained that while genetic vision deterioration induced by retinitis pigmentosa-90 was included in the BRILLIANCE trial, it did not need to be — it is not as rare as LCA, and can be treated more easily and cheaply through gene augmentation.
Another crucial point concerning mutation-specific CRISPR treatments is how much benefit the treatment would offer to the majority of the population.
Dr Raja Narayanan, consultant ophthalmologist and head of clinical research at LVPEI, pointed to the prevalence of the specific gene that was edited in the trial — CEP290.
“The mutation is not found very frequently in India but is estimated to be prevalent in nearly 70 per cent of the population in the West. So, emulating a trial such as this for a very rare gene in India is simply not worth it,” he said.
Additionally, those receiving therapies where the genes are modified inside the body require long-term monitoring for possible side-effects.
Within India, in the gene editing community, and especially ocular genomics, most work is being done around refining and perfecting vectors to deliver more cost-effective gene therapies. Such vectors or carriers are harmless adeno-associated viruses, frequently used as a vehicle to deliver drugs and vaccines into the body.
Private health institutions like Narayana Nethralaya in Bengaluru and research institutes like IIT Kanpur are currently working on improving viral vector delivery for ocular problems.
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How else does CRISPR help?
One of the most effective uses of CRISPR therapy is in immunotherapy — to reprogram the body’s immune system cells to begin identifying cancer cells and killing them. For the first time in 5,000 years of recorded history, humans have made active progress towards actually curing cancer. Immunotherapy can target cancer cells precisely, and leave regular cells be, unlike chemotherapy and radiation, which are the most effective treatments yet.
The massive potential in this area of development is reflected by the setting up of India’s first dedicated immunotherapy facility at IIT Bombay. Inaugurated last month, the facility treats those suffering from leukaemia and lymphoma, both forms of blood cancers for which the therapy works best.
CRISPR gene therapy is also being used to treat genetic deafness.
An 18-month-old toddler in the UK, named Opal Sandy, has become the first person to have her hearing restored by gene therapy after a virus delivered a copy of her gene to her inner ear.
But despite recent advances, gene therapy in the form of both modification and augmentation is still largely inaccessible, owing to its astronomical costs. For drugs like EDIT-101, costs are even higher, primarily because these therapies require personalisation of individual drugs to existing mutations in a patient.
CRISPR trials: The challenges
Many in India would like to begin exciting, potentially complicated CRISPR trials, but regulatory authorities play a huge role in how they come about, just as they do in the rest of the world. However, Narayanan points out that several treatments that generate a lot of international buzz are actually less efficacious and just happen to get more limelight.
“At the end of the day, the [experimental gene therapy trials] results have not been great,” he said.
Narayanan added, “If someone has to pay five crore rupees or so out of pocket, there at least should be an assurance of substantial improvement and its certainty. After treatment, it is not like those who had various forms of blindness were completely cured. They did not become independent, they can’t drive.”
However, he said that the BRILLIANCE trial results show a “dramatic improvement” of vision and are a “great beginning”.
The international research community is still only at the cusp of genetic editing, with cutting-edge tools like CRISPR-Cas9 offering more and more chances for humans to play God — responsibly. Long-term monitoring of genetic changes being done today offers the promise of better healthcare for future generations.
(Edited by Mannat Chugh)
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