Home » Clinical Trials of Gene Therapy for Leber Congenital Amaurosis » The Research Road: Gene Therapy for Leber Congenital Amaurosis
The Research Road: Gene Therapy for Leber Congenital Amaurosis
Scientific discovery is a process, a sometimes long and arduous journey that can be rewarded with incredible breakthroughs. This is the story of a rare inherited retinal disease that devastates the vision of young children and how researchers have discovered a treatment that holds so much hope.
Retina photo of a patient with Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood. Special gene testing is necessary to determine if the patient has the RPE65-associated type of the disease.
1869
Dr. Theodor Leber (1840-1917), German ophthalmologist, first describes what is now known as Leber congenital amaurosis, an inherited retinal disease that causes severe visual impairment early in childhood
1932-34
George Wald, Ph.D. first identified vitamin A in the retina during a National Research Council fellowship in biology
1965
Human adeno-associated virus (AAV) was discovered.
1967
Dr. George Wald, Harvard University, received The Nobel Prize in Physiology or Medicine for his discovery of the role of vitamin A in the visual process
1984
Drs. Nicolas Muzyczka and Paul Hermonat, published an article demonstrating that adeno-associated virus (AAV) can be used to introduce foreign DNA into human and murine tissue culture cells.
1990
Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation began work on RPE-specific monoclonal antibody.
1993
Dr. T. Michael Redmond of the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation cloned RPE65, a protein necessary for processing vitamin A in the visual cycle
1997
RPE65 gene mutations identified as the cause of congenital blindness in some children with Leber congenital amaurosis
1998
The knockout mouse model was created by Dr. T. Michael Redmond's team in the NEI's Laboratory of Retinal Cell and Molecular Biology, Section on Gene Regulation and established RPE65's role in vitamin A metabolism
1998
RPE65 gene mutation was discovered as causing congenital blindness in Briard dogs
2001
NEI-supported researchers at the University of Pennsylvania and University of Florida restore vision in a Briard dog using gene transfer RPE65 therapy
2001
NEI/NIH expands support for pre-clinical studies of RPE65 gene therapy development
2005
Restored vision in Briard dog persists longer than four years following RPE65 gene transfer
2007
NEI-supported RPE65 human clinical trial began. This open label, single dose, dose escalation study is designed to assess the safety of using a modified adeno-associated viral vector (rAAV2-hRPE65) to deliver the normal RPE65 gene to the retina.
LCA as I was mentioning is an inherited retinal degeneration but it's unusual it's severe it affects children early on. Most retinal degenerations manifest themselves a little bit later in life, many times in the teens, 20s and 30s. And I think that's one of the defining characteristics of LCA although there are other inherited severe forms of retinal degeneration that are similar to LCA. There are many different or at least a set of genes that have been identified to cause LCA. The most common is the RPE65 gene. This is a gene that produces a protein that helps process vitamin A in the cells that nourish the retina. Those cells are called the retinal pigment epithelial cells or RPE cells for short. And we know in these patients because of these mutations it doesn't produce enough of vitamin A, which is important for allowing the visual proteins that detect light to sense light.
- Principal Investigator: Dr. Samuel Jacobson, University of Pennsylvania
- Principal Investigator: Dr. Barry Byrne, University of Florida
- Gene Vector Specialist: Dr. William Hauswirth, University of Florida
- Surgeon: Dr. Shalesh Kaushal, University of Florida
LCA as I was mentioning is an inherited retinal degeneration but it's unusual it's severe it affects children early on. Most retinal degenerations manifest themselves a little bit later in life, many times in the teens, 20s and 30s. And I think that's one of the defining characteristics of LCA although there are other inherited severe forms of retinal degeneration that are similar to LCA. There are many different or at least a set of genes that have been identified to cause LCA. The most common is the RPE65 gene. This is a gene that produces a protein that helps process vitamin A in the cells that nourish the retina. Those cells are called the retinal pigment epithelial cells or RPE cells for short. And we know in these patients because of these mutations it doesn't produce enough of vitamin A, which is important for allowing the visual proteins that detect light to sense light.
2008
First cohort of the NEI-supported RPE65 human clinical trial completed. (Three patients treated.) Promising results published in Proceeding of the National Academy of Sciences (September 22) and Human Gene Therapy (September 7).
Dr. Samuel Jacobson shares what patients report seeing after gene therapy:
So what do they notice, well, generally speaking within a week, they will tell you that they see things brighter. They will tell you that they see things. Some are more specific observers and others are less specific. Some will tell you where exactly where they see it brighter. One person calls it a headlight. The headlight got turned on on day five and it just hasn't turned off. That's a really interesting headlight. I mean it's not a headlight that's there without vision, stimulation but there's a view of the world through that headlight that wasn't there before.
Dr. Samuel Jacobson shares what patients report seeing after gene therapy:
So what do they notice, well, generally speaking within a week, they will tell you that they see things brighter. They will tell you that they see things. Some are more specific observers and others are less specific. Some will tell you where exactly where they see it brighter. One person calls it a headlight. The headlight got turned on on day five and it just hasn't turned off. That's a really interesting headlight. I mean it's not a headlight that's there without vision, stimulation but there's a view of the world through that headlight that wasn't there before.
