Gene Editing Restoring Sight in Blind Children

A clinical trial which used CRISPR-Cas9 gene editing, named BRILLIANCE, treated patients with Leber Congenital Amaurosis (LCA). LCA is a genetic blindness that is caused by CEP290 gene mutations. In this experiment, fourteen patients, which included two under 17 years old, received surgical injections of a gene editing agent. According to the study published in the New England Journal of Medicine almost half of the participants noted having a significant increase in their visual quality.

Visual improvement was tested in a variety of ways, such as testing how bright a light needed to shine to be detected. Another test was navigating a physical maze to test how easily patients could find their way around. Out of the fourteen patients, eleven of them displayed improvement in at least one of the many tests, and six improved in two or more. More importantly, six of the participants reported experiencing better vision related to seeing color, also called cone-mediated vision. Cones are the type of visual receptors responsible for processing color.

So far the injection of the gene editing agent has shown no significant side effects that would prove this treatment to be harmful. The study's success provides hope for those with genetic forms of blindness as more effective gene editing agent injections could lead to a potential restoration of vision. However, this method of gene editing injections could be used in many other genetic disorders, which makes understanding its methods so much more important for the development of genetic medicine. This study could be a foundational pillar for the medical treatment of genetic disorders as a whole, not just in the field of ophthalmology.

https://www.pennmedicine.org/news/news-releases/2024/may/gene-editing-improves-sight-in-children-treated-for-blindness

https://medlineplus.gov/genetics/understanding/genomicresearch/genomeediting/#:~:text=CRISPR%2DCas9%20was%20adapted%20from,segments%20known%20as%20CRISPR%20arrays.

https://medlineplus.gov/genetics/condition/leber-congenital-amaurosis/

https://medlineplus.gov/genetics/gene/cep290/

Restoring Vision Loss Caused by Leber Congenital Amaurosis Using Gene Therapy

     The article begins by explaining a unique cause of vision loss in both adults and children. A rare inherited condition called Leber Congenital Amaurosis, more specifically LCA1, is the result of a mutation in the GUCY2D gene. This gene plays a crucial role in producing the proteins that facilitate vision.  LCA1 generally affects people in early childhood. LCA1 affects roughly only 100,000 individuals worldwide. 

    Researchers at the University of Pennsylvania believe they can inject a new unmutated gene into the retinas of adults and children diagnosed with LCA1-- which could improve vision by 100-1,000 times their original vision.  A total of fifteen patients diagnosed with LCA1- twelve children and three adults-- participated in a new study. All subjects had vision equal to or below 20/80 [a normally sighted individual could see an object at eighty feet, whereas these individuals could only see that same object at twenty feet.] 

    A newly developed form of gene therapy called ATSN-101, developed by Atsena Therapeutics, was performed under a phase two trial designed to gauge the treatment's safety and dosages. Hence, the injected therapy was examined under three varying dosages. Three adults received low and medium dosages of ATN-101, once the lower doses were cleared and assessed, three children and three adults received a high dosage of ATN-101. The patients were tested on their ability to navigate through a dimly lit pathway, read eye charts, undergo "light flash" tests performed in dark environments, and other eye performance exams to assess the results.  The end result was an improvement in vision nearly immediately, usually, within a month, improvements were seen, and treatments lasted around a year. Two out of the nine patients' sight improved by 10,000-fold compared to their sight prior to treatments. Any side effects observed using the therapy were generally related to the surgery itself that was used to implant the gene therapy; such as temporary acute hemorrhages in the eye and or temporary eye inflammation. 

I found this article interesting as I had never heard of the condition Leber Congenital Amaurosis or knew what caused this disease; a mutation in a specific gene called LCA1.  This article piqued my interest from the beginning, and after skimming it, I grew more interested in the topic.  I found it particularly interesting when the authors mentioned that a team of researchers had prior success applying gene therapy to correct another form of Leber Congenital Amaurosis caused by a mutation in another gene referred to as CEP290.  Overall, I found the research in this article both enlightening and hopeful, not only as a viable treatment for individuals with this condition but as a reaffirming promise for the field of gene therapy in treating other conditions/diseases in medicine. 

Blinding Disease Has Similar Causation Gene in Humans and Canines

The cilia of mammals is the sensory organelle of our cells. Diseases that affect the cilia are called ciliopathies. A ciliopathy that causes both severe kidney disease and Leber congenital amaurosis, which is a blinding disease, is Senior-Løken Syndrome. The University of Pennsylvania researchers identified a dog with a similar blinding condition as Senior-Løken Syndrome. When the disease course was studied between human and canines, there were many similarities as well. The same gene was involved for both the human and the canine: NPHP5. An important observation from the dogs diagnosed with Senior-Løken Syndrome and humans diagnosed with the same ciliopathy is that despite functional vision during the day, the photoreceptor cells that function during daylight were still present. The cone cells were still preserved, but the rod photoreceptors were deteriorated. These cone cells, in both humans and canines, stayed preserved until very late in the course of the disease. NPHP5 was studied in the mutant canines and it was found that 33 other genes were affected by this mutation, some of which caused two other forms of retinal degeneration. However, unlike in humans where it can cause severe kidney disease when NPHP5 is the causation gene, the kidney structure and function was unaffected. This discovery is leading to the research of gene therapy for the mutant NPHP5 in canines, which will eventually lead to the advancement in gene therapy for humans with Senior-Løken Syndrome.

Finding connections between canine and human diseases is a reminder that we are all linked. I think that finding the causation gene NPHP5 and being able to test gene therapy in canines on that gene proves that animal models are a key role in furthering treatment and therapy of diseases. This is beneficial to the animals and to humans. Animal research is important, although sometimes an unpleasant topic to speak of, when we talk about furthering medical breakthroughs. Thinking of dogs as an animal model is hard for people because of their domestication as our household pets. However, humans and their pets are living longer, happier, and healthier lives due to the strives that animal models provide the biomedical field. This article interested me because the connection between animals and humans never fails to seize to amaze me on just how intertwined we are.

Source:

University of Pennsylvania. "Binding Disease In Canines and Humans Share Causative Gene, Pathology" ScienceDaily. ScienceDaily, 29 August 2016.