Listen to this page using ReadSpeaker

ARVO 2014: Three Promising CEP290 Gene Therapy Alternatives

Renee Ryalls explains the dual-AAV gene therapy she's developing.While gene therapies for retinal degenerative diseases are making groundbreaking strides in both human and laboratory studies, the most widely and successfully used human-engineered virus for delivering replacement genes to retinal cells — the adeno-associated virus, or AAV — has one significant limitation. It can’t deliver relatively large genes, namely those larger than about 4.5 or 5 kilobases (kb). (Bases are the building blocks of a gene, and its size is expressed in kilobases.)

This capacity limitation has been a challenge for researchers trying to develop gene therapies for a number of retinal conditions, including those caused by mutations in the gene CEP290, which happens to be a little more than 8 kilobases.

CEP290 mutations are the leading cause of Leber congenital amauorsis (LCA), a retinal degenerative disease that often leads to severe vision loss in young children. CEP290 defects can also cause syndromic conditions — e.g., Bardet-Biedl, Joubert and Senor-Loken syndromes — which result in a constellation of symptoms, including LCA.

At the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO), it is great to see reports from FFB-funded scientists who are developing a number of creative approaches to overcoming the delivery challenge for CEP290.

Take, for example, Erin Burnight, Ph.D., at the University of Iowa, who is using a lentivirus, which has the cargo capacity of about 9 kilobases, to deliver copies of CEP290 to stem cells derived from the skin of an LCA (CEP290 mutations) patient. Dr. Burnight demonstrated that the treatment effectively corrected the genetic defect in the cells. An advantage of the lentivirus is that it’s already being used in gene-therapy human studies for age-related macular degeneration, Stargardt disease and Usher syndrome type 1B.

Another approach discussed at ARVO involves delivering CEP290 in two packages. Renee Ryalls, at the University of Florida, is developing a dual-AAV gene therapy to deliver CEP290 to human cells in two packages. She and her team continue to fine-tune the approach to get the gene to re-assemble once delivered and function normally.

Alejandro Garanto, Ph.D., at the Radboud University Medical Centre in the Netherlands, is developing what are known as antisense oligonucleotides, or AOs, to correct the defective messaging that occurs with certain types of CEP290 mutations. At ARVO, he discussed how his therapy worked successfully in LCA patient cells.

Two important points about all three of these studies: 1) They are important steps toward clinical trials of emerging therapies; and 2) the approaches have the potential to work for treating retinal diseases caused by mutations in other large genes, including USH2A (Usher syndrome) and EYS (retinitis pigmentosa).

A final note: These aren’t the only alternatives for delivering large genes. Check out articles on the work of Muna Naash, Ph.D., David Schaffer, Ph.D., and Luk Vandenberghe, Ph.D., to learn more about the other options.

Pictured, above: Renee Ryalls at ARVO, explaining the dual-AAV gene therapy she’s developing.

 

 

Please follow and like us:
0

19 Responses to 'ARVO 2014: Three Promising CEP290 Gene Therapy Alternatives'

  1. Patty Bushland says:

    Keeping these researchers in our prayers! God speed as my little girl is 8 years old now and we were told she would probably be seeing by the time she was 10. Thank You for all your hard work! It is appreciated by many!

  2. Kasiane Vasilopoulos says:

    please let me know when the trial for Stargardts will take place & where.

    Thank you,
    Kasiane Vasilopoulos

  3. Brigid Martin says:

    I think it’s amazing how this work is progressing,there are some very talented researchers. I too would be interested to know when the trials for Stargardts take place and where.

    Thank you

    Brigid Martin

  4. chris says:

    I have a grandmother, a farher, and a sister who all suffer from rp who would be interested in this research. Please email me and I can get you in touch with them.

    • EyeOnTheCure says:

      There are three main types of RP: recessive, dominant and X-linked. Given that your grandmother, father and sister all have RP, suggests that they may have the dominant form of RP. However, it is possible that they have the X-linked form as well. Accordingly, they may want to consider trying to obtain a molecular diagnosis (gene identification). For more information on genetic testing, please see:
      http://www.blindness.org/sites/default/files/pages/pdfs/Genetic-Testing-Booklet-V5.2-20151023.pdf

      Your family members 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 specific diseases. For more information on “My Retina Tracker” please see the following web link:
      https://www.myretinatracker.org/

  5. Aubrey Eubanks says:

    My grandfather, 65, has been diagnosed with Stargardt’s and Retinitis Pigmentosa for all of my lifetime now, I will turn 19 in July. Please, let me know when this trial is going to be available. He is not fully blinded, but his vision has continued to deteriorate.

    • EyeOnTheCure says:

      If your grandfather has Stargardt and RP caused by mutations in the ABCA4 gene, he may be able to get into one of the human clinical trials. The Foundation Fighting Blindness is partnering with Sanofi to conduct a gene therapy clinical trial for Stargardt disease in Oregon and Paris, France. For more information on this trial, see the following link:
      http://clinicaltrials.gov/ct2/show/NCT01367444?term=stargardt&recr=Open&no_unk=Y&rank=2

      Before one can participate in any gene therapy trial they must first obtain a molecular (genetic) diagnosis. 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

      “My Retina Tracker” is a free registry that can help people 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/

      To learn more about the progression of Stargardt disease, The Foundation Fighting Blindness is also conducting a natural history study, referred to as PROSTAR. For more information on PROGSTAR, please see the following link: http://progstar.org/

      You may be interested to know that there is a “Stargardt – Macular Degeneration” Facebook page where you can communicate with other families affeced by Stargardt disease. Here is the link:
      https://www.facebook.com/groups/Stargardts/
      Here is a list of pharmaceutical companies developing treatments for Stargardt Disease:

      Acucela,( http://www.acucela.com/) is a Seattle-based biotechnology company that is developing several drugs for retinal diseases such as AMD, dry eye, diabetic retinopathy, retinopathy of prematurity and Stargardt disease. Acucela’s visual cycle modulators (VCM) reduce the activity of the rod visual system — in essence, “slowing it down” and reducing the metabolic load on the retina. Reducing the speed of the visual cycle has been shown to protect the retina from light damage and reduce the accumulation of retinal-related toxic by-products, including A2E, which is implicated in both Stargardt disease and dry AMD. The Company’s lead investigational compound (Emixustat™) is currently in Phase 2b/3 trials for dry AMD and has potential for also treating Stargardt disease. In addition, Acucela recently licensed the rights to fenretinide and is considering continuing development of this drug for Stargardt and dry AMD.
      Visum Therapeutics, (http://www.visumtherapeutics.com) Visum Therapeutics is developing a small molecule therapy to treat Stargardt’s disease. Visum’s novel approach proposes to develop drugs that will temporarily control levels of A2E in the eye and preserve the natural vision cycle, leading to a therapeutic treatment. Visum has discovered a unique chemical approach to sequester rather than eliminate A2E. Through this process, 25 diverse FDA approved drugs demonstrating both mechanistic and in vivo efficacy have been identified. Visum has identified a lead compound, VSM 20R, which is an enantiomer of an FDA approved drug that demonstrates complete retinal protection in preclinical studies. Visum plans to conduct Phase I and Phase II clinical trials in the near future.
      Alkeus, (http://alkeus.com/) Alkeus has developed a form of vitamin A that upon light interaction, does not form toxic vitamin A metabolites and A2E. Alkeus’ lead compound, ALK-001, is an oral compound with a well-understood mechanism of action. ALK-001 was specifically designed to treat Stargardt disease by preventing the formation of these toxic vitamin A dimers in the eye. ALK-001 has been cleared by the U.S. Food and Drug Administration (FDA) to start a clinical trial.

      Advance Cell Technology (http://www.advancedcell.com/), a Santa Monica-based biotechnology company, has developed an RPE cell line that is derived from embryonic stem cells (ESC). In collaboration with FFB-funded researcher, Dr. Raymond Lund, ACT showed that the subretinal transplantation of ESC-RPE cells in a rat RP model resulted in 100% visual function rescue. Functional rescue was also achieved in the Stargardt mouse model with near-normal functional measurements recorded at more than 70 days. In 2011, a Phase 1 clinical trial was initiated to evaluate ESC-RPE cell transplantation in individuals with Stargardt disease.

  6. tanvi says:

    hi,my nephew is 14 years old and he is diagnosed with stargadt disease 3 years back.now his left has no vision but right ete has 30% vision.please help me by giving me deatils of therapies or whatever treatment could be done.

    • EyeOnTheCure says:

      You will be happy to know that the Foundation Fighting Blindness is partnering with Sanofi to conduct a gene therapy clinical trial for Stargardt disease in Oregon and Paris, France. For more information on this trial, see the following link:
      http://clinicaltrials.gov/ct2/show/NCT01367444?term=stargardt&recr=Open&no_unk=Y&rank=2
      Before one can participate in any gene therapy trial they must first obtain a molecular (genetic) diagnosis. 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
      “My Retina Tracker” is a free registry that can help people 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/
      To learn more about the progression of Stargardt disease, The Foundation Fighting Blindness is also conducting a natural history study, referred to as PROSTAR. For more information on PROGSTAR, please see the following link: http://progstar.org/
      You may be interested to know that there is a “Stargardt – Macular Degeneration” Facebook page where you can communicate with other families affeced by Stargardt disease. Here is the link:
      https://www.facebook.com/groups/Stargardts/
      For your information, below is a list of biotech / pharmaceutical companies that are developing treatments for Stargardt Disease:

      Acucela,( http://www.acucela.com/) is a Seattle-based biotechnology company that is developing several drugs for retinal diseases such as AMD, dry eye, diabetic retinopathy, retinopathy of prematurity and Stargardt disease. Acucela’s visual cycle modulators (VCM) reduce the activity of the rod visual system — in essence, “slowing it down” and reducing the metabolic load on the retina. Reducing the speed of the visual cycle has been shown to protect the retina from light damage and reduce the accumulation of retinal-related toxic by-products, including A2E, which is implicated in both Stargardt disease and dry AMD. The Company’s lead investigational compound (Emixustat™) is currently in Phase 1 safety trials for dry AMD.

      Alkeus, (http://alkeus.com/) Alkeus has developed a form of vitamin A that upon light interaction, does not form toxic vitamin A metabolites and A2E. Alkeus’ lead compound, ALK-001, is an oral compound with a well-understood mechanism of action. ALK-001 was specifically designed to treat Stargardt disease by preventing the formation of these toxic vitamin A dimers in the eye. ALK-001 has recently completed a Phase 1 safety trial and they are now recruiting patients for the Phase 2 study in the U.S.

      Ocata Therapeutics (Previously: Advance Cell Technology (http://www.ocata.com/), a Santa Monica-based biotechnology company, has developed an RPE cell line that is derived from embryonic stem cells (ESC). In collaboration with FFB-funded researcher, Dr. Raymond Lund, ACT showed that the subretinal transplantation of ESC-RPE cells in a rat RP model resulted in 100% visual function rescue. Functional rescue was also achieved in the Stargardt mouse model with near-normal functional measurements recorded at more than 70 days. A Phase I safety trial on 37 patients with Stargardt and dry AMD was recently successfully completed and they are now recruiting patients for the Phase 2 studies.
      Visum Therapeutics, (http://www.visumtherapeutics.com) Visum Therapeutics is developing a small molecule therapy to treat Stargardt’s disease. Visum’s novel approach proposes to develop drugs that will temporarily control levels of A2E in the eye and preserve the natural vision cycle, leading to a therapeutic treatment. Visum has discovered a unique chemical approach to sequester rather than eliminate A2E. Through this process, 25 diverse FDA approved drugs demonstrating both mechanistic and in vivo efficacy have been identified. Visum has identified a lead compound, VSM 20R, which is an enantiomer of an FDA approved drug that demonstrates complete retinal protection in preclinical studies. Visum plans to conduct Phase I and Phase II clinical trials in the near future.

  7. Ravi says:

    I am eagerly waiting for the start of a Human Trial for Stargardt’s. I would like to be posted with the developments regularly.

  8. Ulici Daniela says:

    My daughter have LCA with a mutation CEP290 and y realy need too know when and were a can find a genic therapy for her,because it’s hard to see her looking too mee et non seeing me. Tankyou verymuch

  9. Ashley Reinhart says:

    Very interested in LCA gene mutation CEP290 and when clinical trials will start. Thank you for your hard work and dedication for one day the possibility that my son will see.

  10. Andrijana Kraljacic says:

    My daughter who is 4 years old, has gene mutation CEP290 and diagnose Joubert Syndrome and LCA, and I m very interested in those research and would like to know where can I find informations about trials and gene therapy.

    • EyeOnTheCure says:

      Dear Andrijana, You should consider enrolling your daughter in FFB’s “My Retina Tracker”, a free registry that monitors clinical trials that are recruiting for various retinal diseases. 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. Finally, please stay tuned into FFB’s website which is revised weekly to reflect any new research breakthroughs.

  11. Margaret Donga says:

    Thank you for all effort and I hereby encourage you all to go on. My daughter of 19 has LCA caused by CEP290. We follow all the news around these researches!

  12. Mrs. Jacqueline P Marshall says:

    My grandson is thirty four years old. He has been deaf since being a baby.
    Now he has been diagnosed with Ushers disease. He has tried so hard to lead a normal life despite his hearing loss, now the thought of losing his eyesight is so sad. Especially as he is the main carer of a lovely baby girl.
    If there is any help for him available, could you please contact me. My grandsons name is Benjamin French. Thank you

Leave a Reply

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

*