Path To A Cure

                            
 

Since our inception in 2012, Achroma Corp has provided $255,000.00* in grants to DIRECTLY support research efforts in expediting a cure. This page highlights some of the work of prominent researchers currently involved with gene therapy. Gene therapy involves putting a normal copy of the affected gene back into cones of patients. Using Adeno-associated virus (AAV), the native (wild type) genes of the virus are removed and replaced with the gene of interest. This vector is then injected under the patient’s retina. Gene Therapy 101 is summarized in this article by Dr. Shannon Boye: click here to view


 William W. Hauswirth, Ph.D.
 Rybaczki-Bullard Professor of Ophthalmology

Summary of the Hauswirth Lab Achromatopsia Research Progress for 2015

The past year continues exciting progress towards treatment trials for the two major genetic forms of Achromatopsia with both projects achieving tangible milestones that will allow treatment of their first patients in the very near future. As noted last year, Applied Genetic Technologies (NASDAQ: AGTC) has formally assumed the lead in the path to FDA approval and is supporting costs not covered by Hauswirth’s current NIH grants for this purpose. Critically, AGTC would continue this fiscal and logistical support through the patient clinical trials themselves. Support from Achroma Corp. has also been useful in supporting ongoing research within the University of Florida Hauswirth Lab.

For B3 Achromatopsia, the most common form of Achromatopsia in the Western World accounting for about 50% of patients, we are pleased to report that in late 2015 the FDA approved our clinical trial proposal, termed the IND, thus allowing the trial to begin in the first quarter of 2016. Four leading clinics with extensive Achromatopsia experience are collaborating in this effort and include the Casey Eye Institute of the Oregon Health and Sciences University in Portland (Drs. R. Weleber and M. Pennesi), the Chicago Lighthouse for the Blind (Dr. G. Fishman), the Bascom-Palmer Eye Institute of the University of Miami (Dr. B. Lam), and Vitreo-Retinal Associates in Gainesville, Florida (Dr. C. Kay). A site for advanced imaging of cones in all patients is located at the Medical College of Wisconsin in Milwaukee (Dr. J. Carroll). In total, more than 50 patients with genetically confirmed B3 Achromatopsia have been followed for the past one-three years to establish a clear clinical baseline for assessing the safety and therapy of the planned gene therapy treatment. We are now in the final phase of selecting the 24 who will participate in the initial gene therapy study. In parallel our group collaboratively published two research papers with one more just submitted for publication, each being key to gaining FDA approval of our planned clinical trial. 1) We demonstrated for the first time that one element in the gene therapy reagent, termed the promoter, mediates a high level of very specific cone expression of the passenger gene in animals, a necessary prerequisite for an effective gene therapy. 2) Formal animal safety studies carried out to FDA specifications demonstrate that the planned doses of gene therapy reagent are safe. 3) Dr. Carroll through an advanced retinal imagining technique he developed has found that essentially all B3 patients have remaining cone photoreceptor cell bodies that may respond to the planned cone-targeted gene therapy.

For A3 Achromatopsia, which accounts for about 25% of patients in the US and Europe but more than 50% in the Middle East and China, progress has been equally exciting. Advances have been made on several fronts:

1) Over the past year with support from a US-Israel Binational grant a sheep in Israel that we found last year carried the genetics and vision symptoms equivalent to human A3 Achromatopsia have been tested for gene therapy using the human B3 gene. This year we publish a paper showing that the human A3 gene indeed significantly improved not only day vision in these sheep but also the quantity and quality of cone electrical signaling to the brain and the structure of the cones themselves in these sheep. Thus the therapeutic potential of our A3 gene therapy reagent is now clearly established.

2) Through support of an NIH grant to Dr. J. Pang in Hauswirth’s group, we published that a specially designed AAV vector could efficiently restore cone function and structure following injection into the vitreous jelly in front of the retina rather than behind the retina as is currently done. This suggests that in the future there may well be a safer way to deliver the gene therapy reagent to the retina that has less surgical risk.

3) Through a second collaboration with AGTC, A3 patients are currently being studied and enrolled at two centers, one in the US at the Bascom-Palmer Eye Institute of the University of Miami (Dr. B. Lam) and one in Israel at the Hadassah Medical School in Jerusalem (Dr. E. Banin). This is a multi-year natural history study that parallels the B3 patient study outlined above that has been essential for FDA clinical trial approval.

In summary, in the past year we have achieved a key milestone for B3 Achromatopsia: FDA approval to initiate the gene therapy clinical trial. We are currently entering patients in the first phase of the clinical study. For A3 Achromatopsia, demonstration of profound vision therapy in a sheep model will now allow us to advance to formal safety studies this year and hopefully obtain similar FDA clinical trial approval for this genetic form as well later this year or early next year. It is important to point out that all clinical centers continue to see new A3 and B3 patients to ensure that we have a sufficient, well studied group of clinical trial candidates for both forms of Achromatopsia so that we can advance without delay to later phases of the clinical trials when appropriate.
Sheep ACH Video: This fantastic video of sheep (affected with CNGA3 mutation) that were treated with gene therapy (subretinal-injection) as a result of collaboration between University of Florida, Hadassah-Hebrew University Medical Center, The Volcani Center, and the Hebrew University of Jerusalem. Special thanks to Dr. Hauswirth at the University of Florida for sharing it with Achroma Corp.

For each animal you see the ear tag before treatment and its poor performance navigating the maze. Then you see the same sheep (ear tag shown again) after treatment (just one eye) showing its performance markedly improved, actually very nearly normal.

Sheep video:



More about this study can be found HERE (click to read).


Banin E, Gootwine E, Obolensky A, Ezra-Elia R, Ejzenberg A, Zelinger L, Honig H, Rosov A, Yamin E, Sharon D, Averbukh E, Hauswirth WW, Ofri R.”Gene Augmentation Therapy Restores Retinal Function and Visual Behavior in a Sheep Model of CNGA3 Achromatopsia.”Mol Ther. 2015 23:1423-33 PMID:26087757

Research Articles

Gene Therapy in a Sheep Model of CNGA3 Achromatopsia: ARVO 2014  click here to view

History of Gene Therapy: Gene therapy rescues cone function in congenital Achromatopsia:
click here to view

We would like to acknowledge Drs. Andras Komaromy (Michigan St. U.), Gustavo Aguirre (U. Penn) and William Hauswirth (U. Florida), for providing this video. This video demonstrates the effects of gene therapy in treated dogs.

Dog ACH video:

William W. Hauswirth, Ph.D.
Rybaczki-Bullard Professor of Ophthalmology
College of Medicine, Box 100284 HSC
University of Florida
Gainesville FL 32610-0284
Phone: (352) 392-0679
Email: hauswrth@ufl.edu
Website: http://eye.ufl.edu/

                       

Tour of Dr. Hauswirth’s lab at 2014 Achromatopsia
Convention. These girls were lucky enough to get a
mini-biology lesson too!
Featured:  Dr. Christine Kay, Bridget Vissari, Dr. Shannon Boye

 

Joseph Carroll, Ph.D.
Richard O. Schultz, MD / Ruth Works Professor in Ophthalmology
Co-Director, Advanced Ocular Imaging Program
Medical College of Wisconsin

Current research: Given the recent successful restoration of cone function using gene therapy in animal models of achromatopsia, these conditions are logical targets for human trials.  However an important prerequisite is to determine the amount of residual cone structure in these retinas, as the success of the gene therapy approach relies on the presence of cone photoreceptors (even if they are non-functioning). We are currently working on developing new high-resolution, non-invasive imaging tools to assess photoreceptor structure in patients with achromatopsia.  We had previously obtained evidence suggesting that patients with achromatopisa can have a robust population of cones remaining, though it is highly variable across patients and we could not directly confirm these structures.   

Recently, working with Drew Scoles & Alfredo Dubra in the Advanced Ocular Imaging Program (www.mcw.edu/AOIP.htm) we developed a new imaging modality called “split detector” imaging.  Traditional adaptive optics imaging approaches (panels A & D in the figure below) rely on an intact photoreceptor structure for us to visualize the cell, thus interpreting the dark spaces was difficult if not impossible.  The exact same retinal area imaged with the split detector technique (panels B & E) reveal the cone inner segments.  The color merge demonstrates 1:1 correspondence between the dark areas in the conventional image and the inner segments in the split detector image (colored in blue).



This technique provides a non-invasive way to directly quantify the degree of residual cone structure in patients with achromatopsia.  We are now trying to recruit as many patients as possible for imaging so we can better understand how the various genetic forms of achromatopsia correlate with variation in photoreceptor structure.  You can learn more about our research or volunteer directly at www.mcw.edu/AOIP/Participate/How-to-volunteer.htm Patients 5 years and older are eligible to participate and we do cover travel costs to and from Milwaukee for imaging.  

Dr. Carroll’s work on achromatopsia is funded by the National Eye Institute, Foundation Fighting Blindness, Research to Prevent Blindness, and numerous individual donors to the Advanced Ocular Imaging Program.  

Research Articles

A recently published article detailing this new imaging approach can be found HERE

2014: Retinal Structure and Implications for Gene Therapy article can be found HERE

August 2014: A prospective longitudinal study of retinal structure and function in achromatopsia  click here to view

Joseph Carroll, Ph.D.
The Medical College of Wisconsin
Department of Ophthalmology
925 North 87th Street
Milwaukee, WI 53226-4812

Office Phone:  (414) 456-2052
Lab Phone: (414) 456-2054
FAX:  (414) 456-6690
Email:  jcarroll@mcw.edu

Website:  http://www.mcw.edu/ophthalmology/faculty/FacultyProfiles1/JosephCarrollPhD.htm

 

Dr. Joseph Carroll and Raymond An image of Raymond’s cones (large bumps) within his retina as seen by Dr. Carroll’s split-detector adaptive optics.  

Applied Genetic Technologies Corporation (AGTC)

 

Applied Genetic Technologies Corporation (AGTC) is a biotechnology company conducting human clinical trials of gene therapies for the treatment of rare eye diseases, including achromatopsia. AGTC is developing treatments for achromatopsia caused by the two most common genetic mutations causing the disease; CNGB3 and CNGA3.

AGTC uses a virus called adeno-associated virus, or AAV, as a way to deliver a normal copy of a missing or broken gene. The unmodified AAV virus does not cause any illness in people or animals. It is a relatively simple virus that contains only two viral genes. In order to use AAV for gene therapy, the AAV viral genes are removed and replaced by a copy of a normal human gene to create an AAV vector. After the AAV vector enters a cell, the normal human gene in the vector directs the cell to make a normal version of the missing protein, using the cell’s natural protein-making ability.

Normal color vision and fine visual acuity depend on the cone cells in the retina (a light sensitive layer of tissue located at the back of the eye). In achromatopsia, the function of cone cells is severely reduced due to mutations in one of the genes for a protein found in the cone cells. There are animal models for various types of achromatopsia that have a mutation in one of the same genes that causes achromatopsia in humans. Studies using these models have shown that delivering a normal gene copy to the cone cells using an AAV vector can restore cone function in the animals.

Scientists at AGTC are working with others to develop AAV gene therapy vectors for use in humans with achromatopsia. As a starting point, AGTC is making an AAV gene therapy vector containing a normal copy of the CNGB3 gene, because mutations in CNGB3 are the most common cause of achromatopsia. A clinical trial to test this gene therapy vector is starting in 2016 with initial data expected later in the year. To learn more about study specifics or participation, please visit: clinicaltrials.gov/ct2/show/NCT02599922.

AGTC has received orphan drug designation from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for its investigational gene therapy product for the treatment of achromatopsia caused by mutations in the CNGB3 and CNGA3 genes.

In the future they also may develop AAV gene therapy vectors containing a normal copy of other genes that cause achromatopsia.

For more on AGTC’s achromatopsia research and progress, visit agtc.com/index.php/products/achromatopsia.

AGTC
Jeffrey Chulay, M.D., DTM&H
Vice President and Chief Medical Officer
11801 Research Drive, Suite D
Alachua, Florida 32615
Phone: (386) 462-2204
Email: Jchulay@agtc.com
Website: www.agtc.com

 

 

* As of December 2016