By Ruchi Jhonsa, Ph.D.
CRISPR editing is in the news again. But this time it is not for treating cancer. Instead, it is for repairing a mutated gene that causes blindness right from birth. Leber Congenital Amaurosis 10 or LCA10 is a rare disease that affects the vision within the first years of life, resulting in significant vision loss and potentially blindness. Caused by a mutation in 18 different genes, it is the most common cause of inherited childhood blindness, with an incidence of two or three per 10000 live births worldwide.
In the new study sponsored by Editas Medicine and Allergan Alliance at Oregon Health and Science University Casey Eye Institute, doctors injected microscopic droplets carrying the CRISPR editing machinery (AGN-151587) beneath the retina of patient affected by LCA10. The idea is that once the virus delivers the CRISPR machinery inside the photoreceptor cells, it will start editing the genetic defect and make the gene fit again for normal protein production. However, the vision will only improve if one-tenth to one-third of the cells are edited but it may take up to a month to see that change.
It is a glorious moment today for Allergan and Editas, as amidst all the news about the CRISPR off-target effects, it was difficult for them to convince the regulatory authorities about the safety of the treatment. Even though they managed to fend the regulatory concerns before the trial, they are doing everything to ascertain that the drug is safe for the eyes during the trial. The ongoing study involves only a small number of patients with the lowest possible dose in just one eye. Only old patients, who have suffered extensive damage to the eye, are being treated at present, and only one patient has been injected so far.
BRILLIANCE Phase 1/2 Clinical Trial
The trial is a yearlong, open-label, multi-center study that will evaluate the safety and efficacy of AGN-151587 for the treatment of Leber congenital amaurosis 10. Up to five groups of patients in a total of 18 patients with three different dose levels will be enrolled in the study. Patients will be injected with the virus-containing CRISPR construct subretinally to deliver the gene-editing machinery directly to photoreceptor cells. The primary outcome will measure the frequency of adverse events whereas secondary outcome will determine improvement in the vision.
The One Before the First: Ongoing CRISPR Therapy Trials
The CRISPR technology has already been used before in making genetic changes, albeit only outside the human body. Researchers at UPenn are using Multiplex genome engineering, to make T cells more hostile to cancer. Vertex and CRISPR Therapeutics launched a trial early last year that employed the technology to engineer stem cells to treat patients suffering from severe hemoglobinopathies. Sangamo Therapeutics also tried its zinc finger editing technology on patients suffering from metabolic disorders and hemophilia.
Dr. Jean Bennett, a University of Pennsylvania researcher who helped test Luxturna at the Children’s Hospital of Philadelphia said, “The gene-editing approach is really exciting. We need technology that will be able to deal with problems like these large genes.” Dr. Kiran Musunuru, another gene-editing expert at the University of Pennsylvania pointed out that the likelihood that treatment will work is high, based on tests in human tissue, mice, and monkeys. Unlike embryonic editing, this gene-editing tool stays in the eye and does not travel to other parts of the body, so “if something goes wrong, the chance of harm is very small. It makes for a good first step for doing gene editing in the body.”
Everyone is excited about this new trial as it gives hope to families seeking a solution to inherited blindness. “We’re helping open, potentially, an era of gene editing for therapeutic use that could have an impact in many aspects of medicine,” Dr. Eric Pierce a professor of ophthalmology at HMS, who is leading the study says.
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