Q&A: Can gene therapy help a person who is blind from birth due to Leber's Congenital Amaurosis (LCA)?
[Inquiry from Fran]
Dear Dr. Stone,
I'm a 34 year-old girl with Leber's Congenital Amaurosis. I just heard the presentation you gave on April 8 at the New England Ophthalmological Society, available on the eyerounds.org website. I just wanted to thank you for such a great, clear, realistic and optimistic explanation of LCA, molecular diagnosis and the future of gene therapy. What struck me the most was your last comment about the 21 year-old person with only light perception who you think could be an ideal candidate for therapy if he carried the RPE65 mutation. I too only have light perception since birth, and my retinas too look fairly normal, with just a few pigments in the periphery. Usually doctors are uncertain about an adult with no usable vision from birth regaining vision, and I was so happy to hear that you don't rule it out. Unfortunately I don't carry RPE65. So far all known LCA genes have been ruled out for me. I hope so much that new genes are discovered soon, because I can't wait to at least try any form of therapy!
I thank you so much again, and I wish you the best of luck with your work. I hope to meet you one day. You sound like an incredible person.
I hope you don't mind a question: what is your honest opinion about restoring sight to someone blind from birth like me? I know some researchers believe it isn't possible because of the visual cortex's development. But not all agree with that. Do you think seeing light might help? When I talk of restoring sight I just mean being able not to bump into things...
Sincerely,
Fran
[Reply from Dr. Stone]
Dear Fran,
Thanks for your most recent message.
Here is my short answer: I DO believe that some people who have been blind since birth will eventually be able to gain some useful vision from some type of surgical or medical intervention.
Why do I believe this?
1) Briard dogs with Leber's congenital amaurosis (LCA) who are old enough to be visually mature (that is, dogs whose cortical wiring is already complete) are able to regain very useful vision following injection of a viral vector with a functional RPE65 gene under the retina.
2) A 6 year old patient of mine with LCA who can see only hand motions at 1 foot is able to distinguish the border between her yard and her driveway when she is riding her bike. She can also distinguish the edges of doors and curbs bordering roads. She and her parents feel that all of these things help her to function in her daily activities -- that is, that her hand motions vision is "useful" to her.
3) Most patients with LCA have very healthy looking optic nerves even when their retinas look terrible. This suggests that if some new photoreceptive cells can be put into the retina (via some type of stem cell therapy) OR if the remaining ganglion cells can be stimulated (by some type of electrical retinal prosthesis) that the pathways from the eye to the brain are still healthy enough to carry useful information.
4) In 1996, we could identify the disease causing mutations in ZERO percent of patients with LCA. In 2005, we can identify disease causing mutations in over 50% of patients!
5) in 1984 (prior to the invention of the polymerase chain reaction) we could analyze a single gene for mutations in perhaps 5 to 10 people per year. Today, our laboratory can study a single disease causing region of a gene in 2500 people in a single day. This was made possible when a scientist named Kary Mullis figured out how a little microbe that lives in hot springs copies its DNA and then harnessed that microbe's DNA synthesizing machinery to do our bidding.
6) A tiny zebrafish egg with no visible structure to it can develop into an animal with a retina that is very similar in structure to a human retina in just 72 hours. All of the information needed to make a retina is in that little egg. I believe scientists will be able to learn some of the critical steps in this process and use that knowledge to convert stem cells into functional retinal cells for humans.
The points that I am trying to make are: vision doesn't have to be very good for it to be useful, restoration of vision in large visually mature animals who are "blind from birth" has already occurred, and the overall pace of research progress in the past 20 years is nothing short of breathtaking.
So why do some people say that people who are blind from birth will not be able to have their vision restored? Well, for one thing, all patients are different and a treatment that works for one person (or for a dog) may not work at all for another person. Thus, one cannot promise a given patient that they will recover some vision and they certainly cannot promise them that they will recover it by a certain date. (For example, in 1982, I spent 14 months analyzing 4000 base pairs of DNA from a single individual. I would not have been able to predict that the polymerase chain reaction was going to be developed just three years later and that that would allow us to analyze 4000 base pairs of DNA in 20 people in a single day).
I must say that I myself want to avoid suggesting that cures for retinal degenerative diseases are "just around the corner" because I honestly believe that there is still quite a bit of work to be done to develop useful treatments for most of these diseases. However, I also believe that these treatments will be developed and that in my professional lifetime some people who are born with a non-functioning retina will receive a treatment that will allow them to have ambulatory vision or better. To put it another way, I have hope that this will occur. My favorite definition of the word "hope" is "a desire accompanied by confident expectation". One needs hope in this business whether one is the doctor or the patient and I honestly think that we have lots of realistic basis these days for "confident expectation".
So, that was a long answer to a short but very good question. I appreciate your asking it.
I'm a 34 year-old girl with Leber's Congenital Amaurosis. I just heard the presentation you gave on April 8 at the New England Ophthalmological Society, available on the eyerounds.org website. I just wanted to thank you for such a great, clear, realistic and optimistic explanation of LCA, molecular diagnosis and the future of gene therapy. What struck me the most was your last comment about the 21 year-old person with only light perception who you think could be an ideal candidate for therapy if he carried the RPE65 mutation. I too only have light perception since birth, and my retinas too look fairly normal, with just a few pigments in the periphery. Usually doctors are uncertain about an adult with no usable vision from birth regaining vision, and I was so happy to hear that you don't rule it out. Unfortunately I don't carry RPE65. So far all known LCA genes have been ruled out for me. I hope so much that new genes are discovered soon, because I can't wait to at least try any form of therapy!
I thank you so much again, and I wish you the best of luck with your work. I hope to meet you one day. You sound like an incredible person.
I hope you don't mind a question: what is your honest opinion about restoring sight to someone blind from birth like me? I know some researchers believe it isn't possible because of the visual cortex's development. But not all agree with that. Do you think seeing light might help? When I talk of restoring sight I just mean being able not to bump into things...
Sincerely,
Fran
[Reply from Dr. Stone]
Dear Fran,
Thanks for your most recent message.
Here is my short answer: I DO believe that some people who have been blind since birth will eventually be able to gain some useful vision from some type of surgical or medical intervention.
Why do I believe this?
1) Briard dogs with Leber's congenital amaurosis (LCA) who are old enough to be visually mature (that is, dogs whose cortical wiring is already complete) are able to regain very useful vision following injection of a viral vector with a functional RPE65 gene under the retina.
2) A 6 year old patient of mine with LCA who can see only hand motions at 1 foot is able to distinguish the border between her yard and her driveway when she is riding her bike. She can also distinguish the edges of doors and curbs bordering roads. She and her parents feel that all of these things help her to function in her daily activities -- that is, that her hand motions vision is "useful" to her.
3) Most patients with LCA have very healthy looking optic nerves even when their retinas look terrible. This suggests that if some new photoreceptive cells can be put into the retina (via some type of stem cell therapy) OR if the remaining ganglion cells can be stimulated (by some type of electrical retinal prosthesis) that the pathways from the eye to the brain are still healthy enough to carry useful information.
4) In 1996, we could identify the disease causing mutations in ZERO percent of patients with LCA. In 2005, we can identify disease causing mutations in over 50% of patients!
5) in 1984 (prior to the invention of the polymerase chain reaction) we could analyze a single gene for mutations in perhaps 5 to 10 people per year. Today, our laboratory can study a single disease causing region of a gene in 2500 people in a single day. This was made possible when a scientist named Kary Mullis figured out how a little microbe that lives in hot springs copies its DNA and then harnessed that microbe's DNA synthesizing machinery to do our bidding.
6) A tiny zebrafish egg with no visible structure to it can develop into an animal with a retina that is very similar in structure to a human retina in just 72 hours. All of the information needed to make a retina is in that little egg. I believe scientists will be able to learn some of the critical steps in this process and use that knowledge to convert stem cells into functional retinal cells for humans.
The points that I am trying to make are: vision doesn't have to be very good for it to be useful, restoration of vision in large visually mature animals who are "blind from birth" has already occurred, and the overall pace of research progress in the past 20 years is nothing short of breathtaking.
So why do some people say that people who are blind from birth will not be able to have their vision restored? Well, for one thing, all patients are different and a treatment that works for one person (or for a dog) may not work at all for another person. Thus, one cannot promise a given patient that they will recover some vision and they certainly cannot promise them that they will recover it by a certain date. (For example, in 1982, I spent 14 months analyzing 4000 base pairs of DNA from a single individual. I would not have been able to predict that the polymerase chain reaction was going to be developed just three years later and that that would allow us to analyze 4000 base pairs of DNA in 20 people in a single day).
I must say that I myself want to avoid suggesting that cures for retinal degenerative diseases are "just around the corner" because I honestly believe that there is still quite a bit of work to be done to develop useful treatments for most of these diseases. However, I also believe that these treatments will be developed and that in my professional lifetime some people who are born with a non-functioning retina will receive a treatment that will allow them to have ambulatory vision or better. To put it another way, I have hope that this will occur. My favorite definition of the word "hope" is "a desire accompanied by confident expectation". One needs hope in this business whether one is the doctor or the patient and I honestly think that we have lots of realistic basis these days for "confident expectation".
So, that was a long answer to a short but very good question. I appreciate your asking it.
Regards,
Ed
[Response from Fran]
Dear Dr. Stone,
Again I don't know how to thank you for your reply, and for the way you wrote it. I can't believe someone as busy as you took so much time to write such a detailed mail to me! But I really needed it...I'm sure you know how important contact to doctors can be for some patients...just as important as medical tests and treatments.
I sure wasn't wrong when I said you sounded like an incredible person. What many researchers and patients alike don't understand is that even a tiny bit of vision can be helpful for those who have no vision at all and are even able to function well without it. I have no doubt that your 6 year-old patient can make good use of hand motion vision. I don't consider myself to be totally blind because I see light and that helps me a lot in my mobility, along with being a wonderful and reassuring sight. If I can see well enough to avoid walls that will be in itself great for me :-). So maybe those who rule out vision restoration in congenitally blind adults are referring to good vision, which is something I never even dreamed of...But the brain is plastic, and I'm confident that my brain can learn to see somehow.
I understand nobody knows for sure and nobody can make promises - thank you for being realistic. But I loved your definition of hope, and I will never forget it...
I'm keeping a blog on LCA, and I would like to know if you give me permission to publish your beautiful e-mail, there and on the LCA mailing list, since I feel it will be very inspiring and informative for many. But if you feel uncomfortable with it please don't hesitate to say so.
Also (last question, promise!) is your lab also testing for candidate genes? I've sent my sample to other labs but so far I have no answer. The waiting is really the hardest part..... They say my retinas look fine, my optic nerves also...So I'm dying to try anything! But I guess that until we know the mutation it will be difficult.
Again thanks a million for everything. You're really wonderful, as a doctor and as a person. I truly hope to meet you soon!!
Best wishes,
Fran
Again I don't know how to thank you for your reply, and for the way you wrote it. I can't believe someone as busy as you took so much time to write such a detailed mail to me! But I really needed it...I'm sure you know how important contact to doctors can be for some patients...just as important as medical tests and treatments.
I sure wasn't wrong when I said you sounded like an incredible person. What many researchers and patients alike don't understand is that even a tiny bit of vision can be helpful for those who have no vision at all and are even able to function well without it. I have no doubt that your 6 year-old patient can make good use of hand motion vision. I don't consider myself to be totally blind because I see light and that helps me a lot in my mobility, along with being a wonderful and reassuring sight. If I can see well enough to avoid walls that will be in itself great for me :-). So maybe those who rule out vision restoration in congenitally blind adults are referring to good vision, which is something I never even dreamed of...But the brain is plastic, and I'm confident that my brain can learn to see somehow.
I understand nobody knows for sure and nobody can make promises - thank you for being realistic. But I loved your definition of hope, and I will never forget it...
I'm keeping a blog on LCA, and I would like to know if you give me permission to publish your beautiful e-mail, there and on the LCA mailing list, since I feel it will be very inspiring and informative for many. But if you feel uncomfortable with it please don't hesitate to say so.
Also (last question, promise!) is your lab also testing for candidate genes? I've sent my sample to other labs but so far I have no answer. The waiting is really the hardest part..... They say my retinas look fine, my optic nerves also...So I'm dying to try anything! But I guess that until we know the mutation it will be difficult.
Again thanks a million for everything. You're really wonderful, as a doctor and as a person. I truly hope to meet you soon!!
Best wishes,
Fran
[Reply from Dr. Stone]
Dear Fran,
Thanks very much for the email. I think that your half of the correspondence is at least as useful as my half. Feel free to share it as you like. If it is OK with you, I will also post the main portion of our exchange on our website so that others can see your comments about the usefulness of small amounts of vision. I'll remove your last name and email address to protect your privacy.
We do accept blood samples for candidate gene screening and occasionally find mutations in samples that were pronounced negative by others. If you would like us to look at your sample we would be happy to do so. We could do it on a fee for service or a research basis depending on the speed with which you would like to have it done.
Thanks again for your energetic correspondence. I have enjoyed it.
Regards,
Ed
Ed
Genetic testing for eye diseases is performed on a non-profit basis in Dr. Stone's laboratory: www.carverlab.org
