Tag Archives: Leber’s congential amaurosis

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

Gene therapy for blindness – when dogged determination pays off!

Leber’s congenital amaurosis is a progressive disorder that affects about 3,000 Americans, and hundreds of thousands worldwide, and causes a progressive loss of vision that usually results in blindness. The disease, for which there has until now been no effective treatment, is caused by a mutation in the encoding RPE65, an enzyme which is crucial to the production of the chemical 11-cis retinal that photoreceptor cells in the eye need so that they can respond to light.

In one of my first posts for Speaking of Research last year I discussed on this blog how two teams of scientists at Moorfields hospital in the UK and the University of Pennsylvania had used gene therapy to introduce a functioning RPE65 gene into the eye of patients with Leber’s congenital amaurosis, and only last month Anna Matynia discussed how this treatment employs adenovirus-based vectors that have been developed through years of research in rodents and dogs. While the results of those trials were promising the benefits to most of the patients were modest, which was not all that surprising since the scientists doing the trials knew from their studies of Briard dogs with naturally occurring mutations in the RPE65 gene that the therapy needed to begin early in the course of the disease for maximum benefit. For this reason, and because the therapy appeared safe in the first adult human trials, the team at Pennsylvania decided to include children with Leber’s congenital amaurosis in their next study group.


Briard Dog

The early results of that study have been announced following publication in the medical journal The Lancet, and as expected the greatest benefits have been seen in the children, one of whose eyesight improved to nearly normal, though adults in the study also experienced significant improvement. While this particular therapy will benefit a relatively small number of patients its success and that of early trials of gene therapy for Parkinson’s disease are an indication how gene therapy, a field of medicine that has seen its fair share of hope and disappointment over the past couple of decades, is maturing as scientists have learned from both animal studies and human trials about how to harness this powerful therapeutic approach.

The insights gained through the study of the Briard dog with naturally occurring mutations in the RPE65 gene are a good example of the increasingly close ties between clinical and veterinary medicine, a collaboration that is exemplified by the Comparative Oncology Trials Program which brings together veterinary and clinical oncologists under the leadership of the National Cancer Institute to study cancers that affects both dogs and humans, with a dozen trails of new anti-cancer medications already underway. In the future such trials may play an important role bridging the gap between in vitro and rodent studies in the lab that rely on a relatively limited range of cancer cell lines and the far more diverse cancers seen in the clinic. It is hardly surprising that antivivisectionist groups are opposed to these trials, as our colleagues at Understanding Animal Research point out they are quite happy to put dogma ahead of dogs, but fortunately the majority of veterinarians have a much more positive attitude to animal research.


Paul Browne

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.