Point/Counter

Will gene therapy, stem cell therapy or low-vision devices have a greater impact on patient care for inherited retinal dystrophies in the next 5 years?

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J. Timothy Stout

POINT

Each approach will likely have merit

“Inherited retinal dystrophies” is a heterogeneous group of disorders, and 5 years is a pretty short timeline. While the targeted elegance of replacing a defective gene with its normal counterpart has proven successful, the timing of treatment, the duration of effect, the mechanism of drug delivery and immunogenicity are important questions whose answers may be as heterogeneous as the diseases themselves. For RPE65 deficiency, clearly the answer is “gene therapy” as Spark Therapeutics will likely gain FDA approval for its AAV2-hRPE65 product. While there are a handful of other genes under study at this time, they are probably more than 5 years away from FDA approval. The study of CRISPR-Cas9 gene editing for dominant negative disease and the potential for optogenetic restoration of visual function (in a genome agnostic fashion), while attractive, are at early stages. There are hundreds of genes whose mutation is associated with inherited retinal disease, and given our current pace of acquiring preclinical data, executing human clinical trials and getting FDA approval, it will take time for significant impact. This process needs to be accelerated.

Stem cell therapy, while having the advantage of being genome agnostic, is poorly understood. There is little convincing data to suggest that retinal precursor cells, when introduced into the subretinal space, undergo transformation that recapitulates the elegant and complex synaptogenesis that defines the normal retina.

While the currently approved low-vision devices have benefitted relatively few patients, “next gen” devices are likely to be more effective and less cumbersome. Significant improvement will be required for significant impact.

J. Timothy Stout, MD, PhD, MBA, is Sid W. Richardson Professor, Margarett Root Brown Chair and director of the Cullen Eye Institute at Baylor College of Medicine. Disclosure: Stout reports no relevant financial disclosures.

COUNTER

Gene therapy may have most impact

Which will have more impact on an individual patient’s life? I think gene therapy has the highest chance of doing this given the positive phase 3 results from the Spark Therapeutics trial and the fact that there is a good possibility that that medication may be approved. The actual number of patients is very small, based on incidence. Patients need to have RPE65 or a certain type of Leber’s congenital amaurosis. Although the actual market will be very small in terms of the potential patients, for each individual patient, the potential change in vision will be huge. They are going to have opportunities to see, navigate and live their life better than they would have had if this therapy had never been available.

There are other gene therapies coming down the line. There are gene therapies for Leber’s hereditary optic neuropathy that are being done, therapies for choroideremia, and there are potential therapies that are in development that may also have great potential. Those are very exciting to help individual patients in a big way. It is a small number of people with a big response.

Michael A. Singer

On the other end of the spectrum, there are low-vision adaptable devices by companies such as Eyedaptic, Jordy and eSight. Eyedaptic is using augmented reality while Jordy and eSight use virtual reality. I think these devices will have a significant impact on larger numbers of people as the technology starts to get more sophisticated and interfaces with hand-held tablets and smartphones using direct connections or via Bluetooth. I think these devices will make life for these people significantly better in terms of being able to do their activities of daily living.

Another exciting potential will be second-generation versions of currently available surgically implanted low-vision therapies. These technologies currently in clinical trials offer increased independence and options for more potential patients than their first-generation devices.

Stem cell therapy is very exciting, but the question will be trying to figure out how to create stem cells that will not require significant immunotherapy and obviously developing a delivery method that is safe and effective.

Michael A. Singer, MD, is a retina specialist at Medical Center Ophthalmology Associates of San Antonio, Texas. Disclosure: Singer reports he is a consultant with Spark Therapeutics.

Click here to view the Cover Story for this Point/Counter.

J. Timothy Stout

POINT

Each approach will likely have merit

“Inherited retinal dystrophies” is a heterogeneous group of disorders, and 5 years is a pretty short timeline. While the targeted elegance of replacing a defective gene with its normal counterpart has proven successful, the timing of treatment, the duration of effect, the mechanism of drug delivery and immunogenicity are important questions whose answers may be as heterogeneous as the diseases themselves. For RPE65 deficiency, clearly the answer is “gene therapy” as Spark Therapeutics will likely gain FDA approval for its AAV2-hRPE65 product. While there are a handful of other genes under study at this time, they are probably more than 5 years away from FDA approval. The study of CRISPR-Cas9 gene editing for dominant negative disease and the potential for optogenetic restoration of visual function (in a genome agnostic fashion), while attractive, are at early stages. There are hundreds of genes whose mutation is associated with inherited retinal disease, and given our current pace of acquiring preclinical data, executing human clinical trials and getting FDA approval, it will take time for significant impact. This process needs to be accelerated.

Stem cell therapy, while having the advantage of being genome agnostic, is poorly understood. There is little convincing data to suggest that retinal precursor cells, when introduced into the subretinal space, undergo transformation that recapitulates the elegant and complex synaptogenesis that defines the normal retina.

While the currently approved low-vision devices have benefitted relatively few patients, “next gen” devices are likely to be more effective and less cumbersome. Significant improvement will be required for significant impact.

J. Timothy Stout, MD, PhD, MBA, is Sid W. Richardson Professor, Margarett Root Brown Chair and director of the Cullen Eye Institute at Baylor College of Medicine. Disclosure: Stout reports no relevant financial disclosures.

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COUNTER

Gene therapy may have most impact

Which will have more impact on an individual patient’s life? I think gene therapy has the highest chance of doing this given the positive phase 3 results from the Spark Therapeutics trial and the fact that there is a good possibility that that medication may be approved. The actual number of patients is very small, based on incidence. Patients need to have RPE65 or a certain type of Leber’s congenital amaurosis. Although the actual market will be very small in terms of the potential patients, for each individual patient, the potential change in vision will be huge. They are going to have opportunities to see, navigate and live their life better than they would have had if this therapy had never been available.

There are other gene therapies coming down the line. There are gene therapies for Leber’s hereditary optic neuropathy that are being done, therapies for choroideremia, and there are potential therapies that are in development that may also have great potential. Those are very exciting to help individual patients in a big way. It is a small number of people with a big response.

Michael A. Singer

On the other end of the spectrum, there are low-vision adaptable devices by companies such as Eyedaptic, Jordy and eSight. Eyedaptic is using augmented reality while Jordy and eSight use virtual reality. I think these devices will have a significant impact on larger numbers of people as the technology starts to get more sophisticated and interfaces with hand-held tablets and smartphones using direct connections or via Bluetooth. I think these devices will make life for these people significantly better in terms of being able to do their activities of daily living.

Another exciting potential will be second-generation versions of currently available surgically implanted low-vision therapies. These technologies currently in clinical trials offer increased independence and options for more potential patients than their first-generation devices.

Stem cell therapy is very exciting, but the question will be trying to figure out how to create stem cells that will not require significant immunotherapy and obviously developing a delivery method that is safe and effective.

Michael A. Singer, MD, is a retina specialist at Medical Center Ophthalmology Associates of San Antonio, Texas. Disclosure: Singer reports he is a consultant with Spark Therapeutics.