Tag Archives: LCA

Advancing gene therapy, debunking AR propaganda.

The promise of curing genetic diseases by replacing damaged genes with healthy ones is slowly becoming a reality. One recent story is the development of therapy in humans to reverse a form of childhood blindness called Leber congenital amaurosis, or LCA.

OregonLive reports on the story of Alexe Webb who, soon after birth, was diagnosed with LCA the most common cause of inherited blindness in children. Her doctor, Dr. Richard Weleber, said “With this trial, she has the opportunity to have much better vision. We hope the treatment is very durable, that it will last for many decades, even for life.”

As detailed at the National Eye Institute web site:

The groundbreaking clinical trials to restore vision in patients with LCA rest on 15 years of basic research with animals. Long before the gene transfer procedure could be tested in people, four critical milestones had to be met: the discovery of the RPE65 gene; creation of a mouse model that illustrates the gene’s functions and what happens when it’s missing; development of a safe way to carry healthy replacement genes to the target within the eye; and studies of the procedure in a large animal model — dogs.”


The report continues:

Dogs carrying a nearly identical mutation to Alexe’s were the first test subjects. Within two weeks of treatment, three nearly blind dogs were able to navigate with little problem, Dr. Jean Bennett, a professor of ophthalmology at the University of Pennsylvania Medical School in Philadelphia told the Journal of the American Medical Association in October. The effects of a single injection persisted for more than 10 years in the first dog treated. Researchers learned that retinal cells may be ideal targets for gene therapy because they don’t divide much, allowing replaced genes to persist.”


This isn’t the first time that this use of gene therapy to treat LCA has caught our attention, back in 2009 Anna Matynia wrote a piece which highlighted the value of the briard dog to this research. All in all it is a great example of how gene therapy is starting to change the face of medicine.

The briard dog, crucial to the development of gene therapy for LCA

In other news we reported last week on how the animal rights zealots at PCRM were willing to endanger the lives of preterm babies by attacking an important training program at the University of Washington.  We were pleased to note an editorial in the Seattle Times which comes down firmly on the side of the University of Washington, the Seattle Times clearly recognizes that Dr. Dennis Maycock and his colleagues at the University of Washington are the real responsible and ethical physicians in this debate.

The problem of specialist pediatric training programs coming under attack from AR activists is not however limited to Seattle, PeTA are attempting to close down a similar training program at Primary Children’s Medical Center (PCMC) in Salt Lake City. The Daily Herald has reported how PeTA have resorted to false claims that PCMC have conceded to their demands. Once again doctors have had to confront misleading animal rights propaganda, with Dr. Bonnie Midget of PCMC pointing out that:

There is no simulator for a 2-pound premature infant,We would love it if someone would make one.”


We at Speaking of Research applaud the responsible physicians at the University of Washington and PCMC who brave threats and harassment to stand up for the welfare of their youngest patients.

Dario Ringach and Paul Browne

Breakthrough of the Year (almost!)

As the year draws to a close it’s time to reflect on an exciting year of animal research, and there seems no better place to start than with the top 10 breakthroughs of the year as selected by the prestigious scientific journal Science. Science is of course a general science magazine, and the choices reflect this with research in diverse fields ranging from astronomy to paleontology.

Last year our sister organization in the United Kingdom reported that Science had selected cell reprogramming to produce induced pluripotent stem cells (iPS cells) as their breakthrough of the year.  Since then we have reported how the safety of iPS technology continues to improve while others have discussed exciting research which shows just how powerful the technique is by reprogramming fibroblast cells to generate healthy mice that can themselves produce offspring.

This year the top slot went to the discovery and study of Ardi, a 4.4 million year old ape who promises to shed a great deal of light on early human evolution, though it remains to be seem if she and her kind are a direct ancestor of modern humans.

We did have the consolation that one of the nine runner ups is an area of medicine to which animal research has made an enormous contribution , the return of gene therapy with Science claiming that  this year “… gene therapy turned a corner, as researchers reported success in treating several devastating diseases”. These diseases include X-Linked adrenoleukodystrophy, a usually fatal disease of the brain and nervous system, Leber’s congenital amaurosis, an inherited eye disorder that leads to blindness, and severe combinedimmunodeficiency (SCID)due to a lack of an enzyme called adenosinedeaminase.

Only last month I wrote about the crucial role of research with mice in developing the gene therapy for X-Linked adrenoleukodystrophy, while both Anna Matynia and I have written about Leber’s congenital amaurosis.  However,  we have not yet had an opportunity to discuss the therapy developed for treating SCID  in patients whose immune system has collapsed because they lack an enzyme named adenosine deaminase (ADA) which is crucial for removing toxic metabolites from cells.

A clinical trial published in January by the New England Journal of Medicine (1) reported how an Italian team had successfully treated  children with SCID by harvesting bone marrow stem cells from the boys and treating these cells with a retroviral vector containing the ADA gene that produces adenosine deaminase, and then transplanting the modified cells back into them.  In 5 of the boys the therapy restored normal function and significant improvements in the function of the immune system were observed in the other 5.  This therapy has been a couple of decades in development and one of the key investigators involved in this effort, and indeed in the recent clinical trial,  has been Dr. Claudio Bordignon of the University of Milan. Dr. Bordignon developed techniques that enabled scientists to study the ability of retrovirus transformed bone marrow cells from patients with ADA-SCID  to restore immune function in  the NOD/SCID mice that lack a functioning immune system (2).  This enabled him and his team to develop retroviral vectors that could safely drive the production of adenosine deaminase in bone marrow stem cells that survived for long periods after transplantation and are suitable for use in ADA-SCID patients where they need to function for many years.

It’s great to see an area of medical research that we’ve been following closely over the past year receive this recognition from Science, and we hope that as with iPS cells in 2009 gene therapy continues to show what it can do in 2010.

Paul Browne

1)      Aiuti A. et al.”Gene therapy for immunodeficiency due to adenosine deaminase deficiency.” N Engl J Med. Volume 360(5), Pages 447-458 (2009) DOI:10.1056/NEJMoa0805817

2)      Ferrari G. et al “An in vivo model of somatic cell gene therapy for human severe combined immunodeficiency.” Science. Volume 251(4999), Pages 1363-1366 (1991) PubMed:1848369

Blind Dogs Lead Researchers to Treatments

Leber’s congenital amaurosis (LCA) is a form of blindness that affects about 1 in 80,000 people.  This inherited disease, in which the retina progressively degenerates, results in severe loss of vision, and frequently patients can only see well enough to count fingers or see bright lights.  Unfortunately, many of these patients also experience eye pain from bright lights.  LCA is caused by mutations in a number of genes, including the RPE65 gene.  Currently, there is no treatment for this disease but clinical trials using gene therapy have recently shown some promise.

Today, Lancelot (shown) continues to see well after a single gene therapy treatment in 2000. Credit: Foundation Fighting Blindness.

Today, Lancelot (shown) continues to see well after a single gene therapy treatment in 2000. Credit: Foundation Fighting Blindness.

The ability to deliver a gene using viral gene therapy was successfully demonstrated in rats and mice in the 1990’s.  Given these technical capabilities, it seemed that LCA might be a good target for gene therapy – delivery of the vector to the small space below the retina could deliver a normal copy of the gene exactly where it is needed.  The next question was, could vision loss be prevented in animal models of LCA?   Briards, a type of sheepdog, are predisposed to blindness, and genetic testing showed they often have mutations in RPE65, just like LCA patients.  Delivery of RPE65 using viral gene therapy to these afflicted dogs gave encouraging results:  the dogs had improved vision as shown by their electroretinograms and their ability to navigate obstacle courses in dim light (Acland et al., 2001).

Now, a report in the Human Gene Therapy and a commentary appearing in both the New England Journal of Medicine and Scientific American highlight a Phase 1 clinical trial to treat LCA using viral delivery of a normal copy of RPE65(Cideciyan et al., 2009).  Within weeks of receiving the vector, all three patients could detect dim light, a task they could not previously do.  Importantly, these visual improvements were still apparent 1 year after treatment. Phase 1 clinical trials are specifically designed to test safety of a treatment and to date, viral gene delivery of RPE65 has passed this test.  These three patients have not developed an immune response to the viral delivery system, a critical aspect for efficacy and safety of the treatment.

Studies in animals are also helping to clarify how and when the treatment will be effective. An important consideration is that people or animals need to have a good number of retinal cells left if the gene therapy is to be effective:  this treatment only works before retinal degeneration has progressed too far.  The patients in the clinical trials were adults with some intact photoreceptors, however most LCA patients lose photoreceptors in early childhood.  Studies using mice or dogs of various ages have shown promising results indicating that the younger the animal is treated, they more effective treatment is (Dejneka et al., 2004) .  Consequently, early intervention, before extensive degeneration has occurred, will likely be critical to preventing the severe loss of vision that characterizes this disease.  Additional Phase 1 clinical trials are ongoing and include children with LCA.

Can thes patients that have received RPE65 through gene therapy expect the same prognosis as their canine counterparts?  Only time will tell, but they should be optimistic about their long-term outcomes.  The LCA briard dogs, including Lancelot who was one of the first dogs treated, have shown functional recovery that lasting for more than 7 years.


Anna Matynia

Acland, G.M., Aguirre, G.D., Ray, J., Zhang, Q., Aleman, T.S., Cideciyan, A.V., Pearce-Kelling, S.E., Anand, V., Zeng, Y., Maguire, A.M., et al. (2001). Gene therapy restores vision in a canine model of childhood blindness. Nat Genet 28, 92-95.

Cideciyan, A.V., Hauswirth, W.W., Aleman, T.S., Kaushal, S., Schwartz, S.B., Boye, S.L., Windsor, E.A., Conlon, T.J., Sumaroka, A., Pang, J.J., et al. (2009). Human RPE65 Gene Therapy for Leber Congenital Amaurosis: Persistence of Early Visual Improvements and Safety at 1 Year. Hum Gene Ther.

Dejneka, N.S., Surace, E.M., Aleman, T.S., Cideciyan, A.V., Lyubarsky, A., Savchenko, A., Redmond, T.M., Tang, W., Wei, Z., Rex, T.S., et al. (2004). In utero gene therapy rescues vision in a murine model of congenital blindness. Mol Ther 9, 182-188.