Gene Therapy in Ophthalmology Update 6: First-Ever Clinical Trial for the Autosomal Recessive Form of Retinitis Pigmentosa (arRP) is Underway

It has been difficult keeping up with the changing world of gene therapy in ophthalmology, but thanks to the Foundation Fighting Blindness, I learned yesterday about this new, and first clinical study for treating a rare form of retinitis pigmentosa, underway in Saudi Arabia.

Here is the story, as reported by the FFB’s website:


First Gene Therapy Clinical Trial for Recessive RP is Underway

December 22, 2011 - The field of gene therapy for retinal degenerative diseases is taking a big step forward with the launch of the first-ever clinical trial for people with an autosomal recessive form of retinitis pigmentosa (arRP). The human study, underway at King Khaled Eye Specialist Hospital in Riyadh, Saudi Arabia, is evaluating gene replacement for individuals with mutations in the gene MERTK, which is a frequent cause of arRP in people of Middle Eastern descent.

While the primary goal of the six-participant, Phase I trial is to evaluate the treatment's safety, investigators will also be looking at its effect on vision.

The treatment works by using a manmade adeno-associated virus, or AAV, to deliver healthy copies of the MERTK gene to cells in the retina. The treatment is contained in a tiny drop of liquid that is injected underneath the retina and absorbed by a layer of cells called the retinal pigment epithelium (RPE).

The MERTK gene plays an important role in the daily maintenance and regeneration of photoreceptors, the retinal cells that enable people to see. During sleep, the tips of photoreceptors are shed and disposed of by the RPE through a process called phagocytosis. Subsequently, the tips grow back. However, when the MERTK gene is defective, the disposal and regeneration process doesn't work properly, and debris and waste products accumulate, causing photoreceptor death and vision loss

"It is great to see clinical trials of gene therapy expanding into more forms of retinal disease and targeting additional mechanisms of disease such as defects in phagocytosis," says Stephen Rose, Ph.D., chief research officer, Foundation Fighting Blindness. "If successful, it broadens the range of retinal conditions that are amenable to gene therapy."

Dr. Rose notes that, for years, the Foundation has funded several MERTK and phagocytosis research projects, which helped make the current study possible. In addition, the AAV being used for gene delivery is similar to the one used in clinical trials of gene therapy that have restored vision in children and young adults virtually blind from Leber congenital amaurosis.

The MERTK gene therapy trial is being led by Drs. Kang Zhang of the University of California, San Diego, and Fowzan Alkuraya of King Khaled Eye Specialist Hospital. Dr. William Hauswirth, a Foundation-funded gene therapy development expert from the University of Florida, is also on the study team. His lab developed the AAV used in the trial and carried out preclinical safety studies to gain approval for the trial in Saudi Arabia.


Editor’s Note: I have been trying to keep track of the many pre-clinical and clinical studies underway in this ever changing field. I have put together a table of all of the activities underway that I have been able to identify and offer it to all interested parties. Gene Therapy Companies/Institutions Active in Ophthalmology, Version 8, updated as of yesterday, is available in a Word version to any that request it. Use the Email Me! link shown in the right-hand column.

Gene Therapy in Ophthalmology Update 5: A Complement-Based Gene Therapy for AMD

Selected Reviews of AAO 2011 Retina SubSpecialty Day Presentations

Here is another overview of a presentation made during the Retina SubSpecialty Day Meeting. 

Dr. Elias Reichel, of Tufts University School of Medicine and a founder of Hemera Biosciences, Inc., of Boston, MA, presented on a new approach to treating the dry form of age-related macula degeneration. His paper was based on the research being done by Hemera Biosciences on HMR59, a naturally occurring protein that protects retinal cells from damage by MAC (Membrane Attack Complex), that can be delivered for long-lasting activity via a gene therapy approach. 

HMR59 was developed at Tufts University and subsequently licensed to Hermera Biosciences.  

Complement Regulation via Gene Therapy for Dry AMD 

Elias Reichel, M.D., Professor of Ophthalmology, Tufts University School of Medicine, Boston, MA

HMR59 is a novel therapy primarily targeted at geographic atrophy and other forms of dry age related macular degeneration (Dry AMD) by blocking the final stage of the complement cascade, membrane attack complex (MAC). The complement cascade is implicated via genetic studies as playing a critical role in both wet and dry AMD. 

HMR59 is a gene therapy using an AAV2 vector to express a soluble form of a naturally occurring membrane bound protein called CD59 (sCD59), which blocks MAC. Membrane attack complex is the final common pathway of activation of the complement cascade, and is composed of complement factors C5b, C6, C7, C8 and C9 that assemble as a pore on cell membranes. The MAC pore induces ionic fluid shifts leading to cell destruction and ultimate death. 

HMR59 works by increasing the production of sCD59 by ocular cells. The sCD59 released from the cells will circulate throughout the eye and penetrate the retina to block MAC deposition and prevent cellular destruction. By blocking MAC, the remainder of the upstream complement cascade is left intact to perform its normal homeostatic roles. 

HMR59 will be injected directly into the vitreous cavity in an office setting. Such a procedure is currently performed by all retinal specialists using other medications quite commonly. Using the gene therapy approach offers the opportunity to reduce the number of injections needed over a patient's lifetime as the ocular cells will act as factories to produce sCD59, thus addressing the issue of drug delivery. 

 

In summary: 

• The complement pathway is strongly associated with AMD 

• Membrane attack complex (MAC) is the final step in the complement pathway 

• CD59, a naturally occurring protein, protects retinal cells from damage by MAC 

• Hemera Biosciences has developed a gene therapy which produces soluble CD59 (sCD59) that blocks MAC 

• A single intravitreal injection allows for long term protection from AMD progression 

Hemera Biosciences is currently seeking funding to begin animal toxicology studies to get to a phase 1 study in humans. 

Inquiries for further information should be made to: Elias Reichel, MD.