Hossein Ameri, MD: Will CRISPR Fix Retinitis Pigmentosa?

Currently, patients with retinitis pigmentosa (RP) are limited to receiving retinal prosthesis. It’s the only approved treatment for the condition, and is only suitable for patients with advanced disease and profound vision loss.

Researchers at the University of Southern California’s Roski Eye Institute are searching for novel ways to treat RP before it becomes vision-threatening. Their newest investigational endeavor centers on the use of CRISPR/Cas9 (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated system9), the novel gene-editing technology that received its first approval in 2017 to treat an often lethal blood and bone marrow cancer.

It’s one of many gene therapies on the horizon that could soon open doors for patients with RP. Roski researchers released study results at the 2018 meeting of the Association for Research in Vision and Ophthalmology (ARVO) in Honolulu, Hawaii, showing that they were able to successfully disrupt the RHO gene (the most common gene involved in autosomal dominant RP) in vitro in HEK293 cells.

“The mutation independent gene editing may allow silencing of both normal and mutated alleles of the RHO gene, paving the way for a successful treatment of RP patients with mutations in RHO genes,” researchers wrote.

Hossein Ameri, MD, one of the lead researchers on the team investigating CRISPR/Cas9 as a treatment for RP, sat with MD Magazine at the Hawaii Conference Center to discuss his work.

Hossein Ameri, MD:

Basically the work that we are doing is aiming to treat retinitis pigmentosa, which is a retinal disease that causes blindness eventually.

It starts with night vision and peripheral vision problems and finally causes central vision loss as well. It is caused by over 60 genes that we know now, and these genes have many mutations -- some of them hundreds of mutations.

It is inherited in different forms: autosomal recessive, X-link, and autosomal dominant. In cases of autosomal recessive, the 2 copies of the gene are mutated and they're not functional, so there's no protein. To treat that, all you need to do is insert a functional copy of the gene. That produces the protein of interest.

In autosomal dominant conditions, the mutated gene sometimes has a negative effect. So you have one normal and one mutated gene. You have to actually kind of disable that mutated gene.

So what are we doing? We're trying to use CRISPR/Cas9, which is a new technology that allows precise gene editing, to cut that DNA and then insert a functional copy.

The approach that we're taking is that we directly deliver the ribonucleic protein to this cell using nanoparticles instead of doing genomic insertion of those conditions, because this is more likely to finally result in a practical way of treating this condition.

It's very, very early. We're only doing it on cells, and then after that we have to do the small animals, large animals, phase 1 human clinical trials, phase 2 clinical trial, and phase 3 until it becomes approved.

Of course, I would love to see that everything goes smoothly and we get it right the first time but generally, it's something that you have to spend a lot on, do a lot of modification, improvement, to make it something that is usable.

The same gene therapy that was approved in 2017, they actually cured dogs in 2001 with that method. So look how long it took to get to humans. Hopefully because we already have a system in place, a gene therapy that has been approved, this time will be shorter with the technology that is available now. But it's still, unfortunately, a long way to go.

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