Written by Dr. Mary Sunderland, FFB Director of Research & Education.
I recently had the chance to sit down with Dr. Ben Bakondi, vision researcher and project lead on the recent headline making story: CRISPR corrects retinitis pigmentosa. Based in Los Angeles at Cedars-Sinai Medical Centre’s Regenerative Medicine Institute (RMI), Dr. Bakondi’s research is focused on how to use the CRISPR/Cas9 gene editing approach to develop therapies for retinal degenerative diseases.
We recently profiled the results from this research and were glad to have the opportunity to ask Dr. Bakondi more questions about their significance. Using CRISPR, Dr. Bakondi explained that the team at RMI was the first to demonstrate that a mutated gene (rhodopsin) could be selectively ablated in live animals without harming the non-mutant (wild type) copy. [As an aside – the basic biology background that you need is just the concept that you have two copies of each gene. Some genetic diseases (and traits) are caused by a mutation on one gene (dominant) whereas others are caused by mutations on both copies of the gene (recessive).] This ability to selectively eliminate a mutant gene is great news for anyone living with a disease caused by a dominant mutation. It is possible to fix (or cure) some genetic diseases by destroying the mutated gene and restore “normal” function with just the remaining working gene.
But, there is also hope for those who are living with a recessive gene because CRISPR can be used to fix both copies of mutated genes. This approach is being developed by the biotechnology startup, Editas Medicine, which plans to use CRISPR to delete about 1,000 DNA letters from the CEP290 gene found in the photoreceptors of patients with the inherited blinding eye-disease: Leber congenital amaurosis (LCA). After making this fix, lab results suggest that the gene should be able to function normally.
Indeed, early results are so promising that Editas announced plans to start its LCA clinical trial in 2017 – that’s just a year away. Editas decided to focus on LCA because it is a low hanging fruit that should enable them to demonstrate the therapeutic power of CRISPR. LCA and other rare inherited retinal diseases are appealing to researchers for two key reasons: 1) the exact gene error is often known, and 2) the eye is easy to reach with genetic treatments. Although important scientific questions remain about the effectiveness of CRISPR and the potential for side effects, a promising stream of results from the laboratory are fueling everyone forward.
Dr. Bakondi along with other members in the laboratory of Dr. Shaomei Wang are developing a clear path to the clinic. They are looking for ways to increase the efficiency of their approach by testing various delivery methods to reach more of the retina and by improving the frequency of genomic editing once there. They are also collaborating with clinicians to test if the approach will work on the cells of people living with RP. Together, all of this data will help to move them closer to the clinic. Importantly, Dr. Bakondi has been joining patient Facebook groups and talking with us to learn more about the patient perspective.
How does CRISPR compare to existing gene therapy approaches? Whereas gene therapy is used to add genes, CRISPR is used to edit genes. One of the reasons why the biomedical community is enthusiastic about CRISPR is because of the limits of traditional gene therapy. For example, with gene therapy, it is challenging to deliver a steady supply of a new gene for the lifetime of a patient. In contrast, once CRISPR has been used to “fix” a gene by editing out the mistake, the patient’s own gene is then able to function normally for their lifetime. Also, it is challenging to deliver some genes with a traditional gene therapy approach simply because some genes are too large to fit inside the viruses that are used to deliver the therapy. Gene size, for example, has made it difficult to develop a gene therapy for Stargardt disease and Usher Syndrome. In contrast, CRISPR can edit genes regardless of their size.
In closing, I asked Dr. Bakondi if he would be willing to make a prediction about how many years it would take before the research at RMI was ready for the clinic. He wagered an optimistic guess of three to five years and cautioned that more fundamental laboratory work was still needed. Dr. Bakondi agrees that “false hope is a terrible thing,” but in this case, there are legitimate reasons to be hopeful.