Listen to this page using ReadSpeaker

ARVO 2015 Highlight: A Cut-and-Paste Approach to Fixing Retinal-Disease Genes

gene editingI just returned from the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO), the world’s largest eye-research conference, held this year in Denver. It attracted more than 11,000 scientists and physicians, including many of the 187 retinal researchers funded by the Foundation. The FFB science team and I worked feverishly to learn as much as possible about the latest news from the retinal-research front. It was truly exhilarating—albeit, at times, overwhelming.

One of the hot topics at ARVO this year is a rapidly advancing gene-therapy approach called clustered regularly interspaced short palindromic repeats, or CRISPR. Given that name doesn’t exactly roll off one’s tongue, it’s usually just called “crisper,” as in, “Honey, something in the fridge smells awful. I think the cabbage in the crisper is rotting.”

CRISPR is different from the gene therapies currently in human studies, which involve gene replacement—i.e., delivering copies of a whole new normal gene to replace the defective copies causing vision loss. In contrast, CRISPR is a gene “cut-and-paste” technology. It works like a molecular scissors to cut out the mutated portion of the gene and inserts a healthy piece of DNA.

Think of it this way: Let’s say your car won’t start. You have two options: Buy a new car or fix the part that’s causing the problem. Getting a new car is like gene replacement. Getting a new part to fix the problem—for example, a battery, starter or fuel pump—is like CRISPR.

Both CRISPR and gene replacement have their pros and cons. One big advantage of CRISPR is getting around the problem of delivering large genes—USH2A, for example—that won’t fit in the human-made viruses designed to carry them into retinal cells.

Also, CRISPR may be a simpler approach to treating diseases in which delivering a whole new gene is not necessary, and simply shutting down or repairing the bad gene may be enough to save vision. This is often the case in autosomal dominant retinitis pigmentosa.

The downside to CRISPR, at least at the moment, is that it often doesn’t work efficiently enough to restore vision. Also, it can have unwanted, off-target effects on healthy genes. But progress in overcoming these issues was reported at ARVO, so scientists are getting closer to moving CRISPR gene therapy into the clinic.

Several scientists presented compelling CRISPR research projects at ARVO this year. Ed Stone, M.D., Ph.D., a Foundation-funded investigator at the University of Iowa, gave a nice presentation on how his team used different CRISPR approaches on cells in the lab to correct the retinal disease genes USH2A, MAK and RHO. And they are working on more.

I suspect that, down the road, there will be a role for both gene replacement and CRISPR (and related gene-editing approaches). It will be interesting to see how these alternatives evolve and mature. Given the diversity and complexity in gene mutations that can cause retinal disease, the more options, the better.


25 Responses to 'ARVO 2015 Highlight: A Cut-and-Paste Approach to Fixing Retinal-Disease Genes'

  1. Arun Torgal says:

    Dear Dr. Steve Rose,

    Thank you for publishing such a nice article regarding CRISPER gene therapy. I am a regular reader of your website and have already subscribed as a member of FFB. I am 40 years old, living in Goa, India and am almost completely blind due to retinitis pigmentosa.

    Such news gives me motivation that one day my vision will be restored and its great work by FFB in keeping ongoing research progressive, considering complex issues of funding, technology, etc. Regular updates on the FFB website keeps me motivated and encouraged about retinal research. I havbe full faith in the Scientists and Doctors who are working tirelessly day and night so that all RP patients can one day see.

    Thank you again and please keep up the great work.

    Regards,
    Arun Torgal,
    Goa, India

    • Deepti Manik says:

      Nice to find u motivated. I am mother of two children from North India. My Son , 4.5 yr old has Nystagmus since birth and daughter, 1.5 yr old has Ocular Albinism. Is there any hope you can see on such gene changing. I am really worried

      • EyeOnTheCure says:

        Please see the following list of Medical Centers in India that specialize in rare retinal disease:

        The major institutes are:

        L. V. Prasad eye institute, Hyderabad, Telangana.

        Shankara Netralaya, Chennai, Tamilnadu:

        Aravind Eye Hospital, Madhurai, Tamilnadu

        Battu eye care, Dr. Rajani Battu, Bangalore, Karnataka

        L.V. Prasad eye institute, Bhubaneswar, Orissa

        All India Institute of Medical Sciences, New Delhi

  2. Rashmi says:

    Sir,
    It’s a good news , CRISPR seems promising.
    My 7 yrs old son is diagnosed with Choroideremia .
    Can CRISPR be of any help to him.
    if yes , when . I mean at what age?

    Thank you.
    Rashmi

  3. Jack C Crofoot, Jr. says:

    Dr. Steve what a simple straight-forward explanation of CRISPR. As always Sir you are the man. I am especially excited that they may be able to use this splicing to turn off the bad gene in adRP. And, possibly replace it with proper coding. Thank you again, Sir.

  4. NETTIE KRUGER says:

    My brother is completely blind With the
    Retina teared i bouth eyes is there any hope for him

  5. Ronel Jacobs says:

    I have a father in law that is blind for many years, but recently, he sometimes can read cd names and numbers when the lighting falls a certain way. How is it possible for him just to see certain bits

  6. asim rafi says:

    i am from Pakistan my son has problem of RP. Please guide me for his treatment.I WILL BE GREATFUL.

    • EyeOnTheCure says:

      Your son should know that there are three inherited forms of RP: recessive, dominant and X-linked. If he is not sure which type he has, he should ask his ophthalmologist. For information on inheritance types, please see the following web link to download a PDF document on inheritance:
      http://www.blindness.org/sites/default/files/inheritance_of_retinal_degeneration_-_july_2012.compressed.pdf
      Your son may also want to try to identify his disease gene/mutation. A molecular diagnosis is the most accurate diagnosis possible. With the genetic information you can check the medical databases to see what, if any research is being done. You also may be able to qualify for gene therapy trials that are taking place. For information on genetic testing, please see the following web link to download a PDF document:
      http://www.blindness.org/sites/default/files/genetic_testing_booklet_201311rev.pdf
      Whether your son identifies his disease gene or not, he should consider participating in FFB’s “My Retina Tracker”, a free registry that can help him find out about clinical trials that are recruiting. For more information on “My Retina Tracker” please see the following web link:
      https://www.myretinatracker.org/

      It may also be helpful to periodically check the website: http://WWW.CLINICALTRIALS.GOV which is maintained by the National Institutes of Health and contains a searchable list of clinical trials for most known diseases. Each clinical trial listing will provide you with information on what the study is about, the requirements for participating and contact information.

  7. ern says:

    Hi Doctor,
    I am Ern from Sydney, Australia.
    I was diagnosed with RP 30 years ago and i have little to no ability to perceive light during the day.
    If there is an opening for human clinical trial and subjects are required, i am happy to volunteer myself as a subject.
    Any help or advice you can give me would be greatly appreciated.
    I can be contacted via email.
    Thank you.

  8. sravanthi says:

    My husband has Retinal Pegmentesia.he is 35 years old.he can’t see things at night,dim light,he can’t able to see the side objects.Could u plz guide me for his treatment in New York

    • EyeOnTheCure says:

      Your husband should consider genetic testing to try and identify the disease gene/mutation. A molecular diagnosis is the most accurate diagnosis possible. With the genetic information you can check the medical databases to see what, if any research is being done. You also may be able to qualify for gene therapy trials that are taking place. For information on genetic testing, please see the following web link to download a PDF document:
      http://www.blindness.org/sites/default/files/genetic_testing_booklet_201311rev.pdf
      Your husband should also consider participating in FFB’s “My Retina Tracker”, a free registry that can help you find out about clinical trials that are recruiting for your specific disease. For more information on “My Retina Tracker” please see the following web link:
      https://www.myretinatracker.org/
      It may also be helpful to periodically check the website: http://WWW.CLINICALTRIALS.GOV which is maintained by the National Institutes of Health and contains a searchable list of clinical trials for most known diseases. Each clinical trial listing will provide you with information on what the study is about, the requirements for participating and contact information.

  9. muhammad Aslam Butt says:

    My grand daughter is facing eye vision problem. Doctor said that the pressure is builting well as now she is 7 month old and Doctor also advised to get iris diaphragm by the application it will be better vision for her. Now she can see from the corners of her eyes.

  10. Bassie Thoreau says:

    Human trial results using CRISPR..or cut and paste gene technology..has unimpressive results so far. No vision improvement has resulted. Using bacteria injected into the bloodstream ..this bacteria chops off defective DNA and inserts a corrective gene in every cell of the body. However some cells take up the process but others don’t so chaos is created in the body. The mitochondria of some cells produce the new DNA and the other established cells refuse to co operate. All the body cells need to be in sync. I can’t see this working in the future as some mature cells simply won’t co operate

  11. Jisha says:

    Hi,

    My brother who is 33 years old is suffering from RP. It was diagnosed in his late teens. He is noable to see anything after Sunset and partial peripheral vision during daytime. Is there any hope for him and those patients who have completely lost their. vision,.

    Regards,
    Jisha

  12. Tammy says:

    i have several family members affected by RP. We have worked with a specialist out of Memphis, but he is no longer there. Where do we look for advances?

  13. Kevin says:

    Was just reading about CRISPR today and the breakthrough in a mouse model of autosomal dominant RP with a rhodpsin mutation. Very exciting stuff. As someone who has adRP, this seems like the answer?

    http://www.genengnews.com/gen-news-highlights/crispr-may-help-to-rewrite-rodent-nursery-rhyme/81252215/

  14. Shabaz Chagani says:

    My 2 kids has this genetic desease called LCA”LEBER CONGENITAL AMOURSIS,and the mutated gene is rpgrip1.i m very excited to read about CRISPR,can you pls tells us if CRISPR will treat LCA?.My son is 6 years old and my daughter is 5 years old,any help will be highly appreciated,Thank you and God bless

    • EyeOnTheCure says:

      Recessive null mutations in retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1) gene are the cause of LCA6 and account for 5% to 6% of the total patient population. RPGRIP1 has an essential role in the photoreceptor connecting cilia, and photoreceptors lacking RPGRIP1 are unable to maintain the light sensing outer segments. As a result, patients lose retinal functions at an early age but retain photoreceptors in the central retina well into adulthood thus holding out the prospect for gene augmentation therapies. Laboratory studies in animal models have demonstrated efficacy of gene therapy in slowing disease progression. With further refinement in the design of the replacement gene construct, clinical trials for Leber congenital amaurosis (LCA) caused by RPGRIP1 mutations could be in the offing in the near future. Clustered regularly interspaced short palindromic repeats (CRISPR, pronounced crisper) are segments of prokaryotic DNA containing short repetitions of base sequences. Each repetition is followed by short segments of “spacer DNA” from previous exposures to a virus or plasmid. CRISPR associated proteins (Cas) use the CRISPR spacers to recognize and cut these exogenous genetic elements in a manner analogous to RNA interference in eukaryotic organisms. By delivering the Cas9 nuclease complexed with a synthetic guide RNA (gRNA) into a cell, the cell’s genome can be cut at a desired location, allowing existing genes to be removed and/or new ones added. To my knowledge, CRISPR/Cas9 could be used to treat RPGRIP1 mutations. However, I am not aware of any recent scientific publications where CRISPR/CAS9 has been used in rodent models of LCA caused by mutations in RPGRIP1.

Leave a Reply

Your email address will not be published. Required fields are marked *

*