Ocular treatment likely to become first Gene Therapy approved in US

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Spark Therapeutics has announced positive results from the Phase 3 pivotal trial of its lead gene therapy product candidate, SPK-RPE65, for the treatment of RPE65-mediated inherited retinal dystrophies (IRDs). These results represent the first successful randomized, controlled Phase 3 trial ever completed in gene therapy for a genetic disease.

Converting rods into cones in a model of retinitis pigmentosa (RP) rescues retinal degeneration

Heritable retinal degeneration is a common cause of visual impairment and blindness, affecting millions of people worldwide. Many research groups have focused on targeted gene therapy as a treatment for these diseases. However, inherited retinal diseases can be caused by mutations in any one of more than 200 genes, and the pathogenic mechanisms of various mutations differ greatly. This was the motivating factor in the work by Dr James C Corbo and his team at the Washington University School of Medicine to develop gene-independent therapies that would be more widely applicable. This work has been published in the Proceedings of the National Academy of Sciences.

A major advance in gene therapy for Retinitis Pigmentosa

A paper published in Nature Communications sheds light on why, until now, it has not been possible to effectively restore vision in rd1 mice – the world’s major model for retinitis pigmentosa (RP). This research also demonstrates how a particular type of mutation in this mice was the cause of failure of previous gene therapy attempts.

New therapy holds promise for restoring vision in Retinitis Pigmentosa and Leber Congenital Amaurosis

Scientists from the University of California, Berkeley and Lawrence Berkeley National Laboratory, along with those of University of Pennsylvania, have demonstrated restoration of visual function in animal models that can help restore sight in blind patients afflicted by diseases such as Retinitis Pigmentosa (RP) and Leber Congenital Amaurosis (LCA).

Gene therapy for childhood blindness

Genzyme has announced the establishment of a research collaboration with the University of Florida (UF) and the University of Pennsylvania to develop gene therapy for the treatment for Leber congenital amaurosis type 1 (LCA-1), which is usually diagnosed in children who are less than a year old, and patients remain severely visually impaired for the rest of their lives. This disease, which is the most common cause of childhood blindness, is a group of degenerative diseases of the retina caused by genetic mutations in one of 19 genes currently associated with the disorder. These genes encode proteins that play a variety of roles in the development and function of the retina, and a mutation in any one of them can cause visual impairment.

New genetic mutations in Bardet Biedl Syndrome identified

UK researchers have identified genetic mutations responsible for Bardet-Biedl Syndrome (BBS), a rare condition that causes blindness, opening the door for personalized treatment and tailored gene therapies.

What is Bardet-Biedl syndrome?
Bardet-Biedl syndrome is a disorder that affects many parts of the body. The signs and symptoms of this condition vary among affected individuals, even among members of the same family.

New technique to determine gene carriers for autosomal recessive retinitis pigmentosa

Scientists from Bascom Palmer Eye Institute and Duke University Medical Center have developed a non-invasive technique to determine if individuals carry a gene for the autosomal recessive type of retinitis pigmentosa. 

The work was being presented at the 2014 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO) in Orlando, Florida.

The technique involves collecting a patient's urine and measuring the ratio between specific compounds. The non-invasive process makes subsequent testing clinic-friendly, especially for children being screened.

In search of quantitative biomarkers for the disease, the authors checked on the urinary and plasma dolichol profiles in autosomal recessive RP (arRP) patients and carriers with mutations in the DHDDS gene encoding dehydrodolichol diphosphate synthase, a key enzyme in dolichol biosynthesis. Dolichols are long chain polyisoprenoid alcohols composed of 17-21 isoprene units.

Mutations in the DHDDS gene lead to a characteristic shortening of plasma and urinary dolichols, which, as per the authors of this study, can be used as a functional readout of the enzyme. Urinary and plasma D18/D19 ratios reliably determine if a DHDDS genotype is disease-causing. 

D18/D19 ratio is a viable objective functional biomarker and can be readily adapted as a clinical test for arRP diagnosis and carrier screening with DHDDS or other genetic mutations that impair dolichol biosynthesis.

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UT Arlington researchers exploring better methods for gene therapies to fight the sight-deteriorating disease Retinitis Pigmentosa.

UT Arlington researchers are exploring a better method for initiating certain gene therapies that could better fight the sight-deteriorating disease retinitis pigmentosa. This research is funded by the National Institutes of Health.

Dr Samarendra Mohanty, Assistant Professor of Physics, at UT Arlington, is focused on using near-infrared ultrafast laser beam to deliver genes that allow expression of light-sensitive proteins, called opsins, into specific cells. That proteins’ expression allows researchers to influence neural activity through optical or light stimulation – a technique known as optogenetics.

In the past, the genes have been delivered to cells by virus. That method can have drawbacks, such as immune responses, in addition to the benefits. In Mohanty’s method, a laser beam creates a transient sub-micrometer size hole, which allows for the gene encoding the proteins to permeate through the cell membrane. It can limit the risk of immune response, as well as delivering larger genes than viral methods, he said.

The scientists claim that with the minimally invasive near-infrared method, DNA and other impermeable molecules can be effectively delivered only to the places most required. In retinitis pigmentosa, the peripheral retina begins to lose light sensitivity due to loss of photoreceptors. With this method, a laser can deliver the genes only to the required part of the retina, making those neurons respond to light again. This method will be more effective than a virus, where the genes are delivered everywhere, potentially causing complications in areas that are already working fine.

Optogenetic stimulation also holds promise for influencing neurons in the brain. Scientists, including Mohanty’s research group, are researching ways it could be used to understand how the brain works or to intervene in case of neurological disorders or to affect behavior.

Ultimately, Mohanty’s team has a goal of creating all optical, or light-based, control and monitoring of cell activity. So, in addition to the light-assisted delivery of genes, the researchers also will work on refining methods for stimulating the neural activity using near-infrared and visible light. Some of those methods are described in a recently published paper called “Fiber-optic two-photon optogenetic stimulation,” which appeared in the journal Optics Letters.

Mohanty’s lab at UT Arlington also will use a method called phase-sensitive interferometry, to monitor the changes in neurons that result from the activation by light. The interferometry method is called “label-free” because unlike fluorescence, it uses the change in behavior of light rays, rather than staining, to track changes at the sub-nanometer level.

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New animal model may help develop new treatments for RP

Developing new treatments for diseases such as RP have been difficult for many reasons. Apart from the fact that it was difficult to pinpoint the genetic defect in the disease, lack of an adequate animal model that could be used to test any new treatment to study its effect and follow the effect for a few months has been an underlying problem for many years now.   

Hence the recent publication in IOVS of success in creating a genetically modified mini-pig may help in the development of newer and improved treatment paradigms, and may eventually help lead us to a cure diseases such as retinitis pigmentosa (RP), which is the most common inherited retinal disease in India. The researchers used miniature pigs, weighing about 150 pounds at full growth, instead of the larger pig, since managing the smaller pigs was much more easier. 

This model has been developed by researchers in the Department of Ophthalmology & Visual Sciences at the University of Louisville, along with researchers from the National Swine Resource and Research Center, University of Missouri.

For those from the scientific background, here's the abstract from IOVS. " ... describes the creation of an inbred, transgenic mini-pig that carries a mutant human rhodopsin gene which is expressed in the retina and is associated with progressive loss of light-evoked ERG responses. This is a significant achievement of considerable practical value in an era in which translational activity for retinal diseases is burgeoning. The rationale for generating this pig is laid out well, and the design appears to have multiple advantages over the existing retinal dystrophic pig. There are many rodent models of retinitis pigmentosa (RP) and conditions resembling RP, but what has been lacking is a large animal model that more accurately mimics the situations encountered when treating human patients. One potential animal model is the pig. There is an existing pig model of retinal degeneration (RD); however, a number of factors have made this model difficult to use, including the large size of the animals at the time of degeneration as well as molecular genetic considerations. The article describes the successful development of a genetically accurate RP-like condition in a mini-pig.

This model should prove quite valuable to people working on treatment of RD, including traditional pharmacologic approaches and regenerative strategies, such as stem cell transplantation. The authors evaluated six transgenic founders whose retinal function was studied with full-field electroretinography from three months through two years. Progeny from one founder were generated and genotyped to determine the transgene inheritance pattern. Retinal mRNA was isolated and the ratio of P23H to wild-type pig RHO measured. The result is a powerful new tool for retinal degeneration research that should be of interest to a wide range of workers in that field."

The Pro23His (P23H) rhodopsin (RHO) mutation is the cause for the most common form of human autosomal dominant retinitis pigmentosa (adRP), with a high propensity for disease characteristics to pass to the next generation. This study was focused on establishing a transgenic miniature swine model of RP using this human P23H RHO gene. 

Animal models are used to screen for safety and efficacy of new treatment paradigms for diseases such as RP, which includes newer treatment modalities such as medications, stem cell therapies, gene therapy, and the artificial retinal prosthesis.

The prevalence of RP in India is considered to be significantly higher compared to other nations. With some small sample studies indicating that RP may affect about 1 in 1000 in some areas, to almost 1 in 500 in some rural areas in India, we potentially have a population of about a million RP patients. 

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Success in clinical trial brings researchers closer to cure for blindness

Researchers at Hadassah Hospital in Israel, led by Dr. Eyal Banin, have completed a clinical trial that tested the use of gene therapy to restore sight to patients suffering from Leber's Congenital Amaurosis (LCA). Dana and Yossi, two participants in this study, suffer from Leber's Congenital Amaurosis (LCA), the most severe form of all inherited retinal dystrophies causing congenital blindness. Like others affected, they have experienced severe visual impairment since birth. LCA sufferers experience poor night vision, low visual acuity and a constricted visual field. This low vision continues to deteriorate, leading to total blindness. Other symptoms may include crossed eyes, roving eye movements, unusual sensitivity to light, and/or cataracts. LCA is usually inherited as an autosomal recessive genetic condition. Those with LCA suffer in darkness, without sight and without hope. Until now.

Dr. Eyal Banin, MD, Ph.D., at the Center for Retinal and Macular Degeneration at Hadassah University Medical Center, in collaboration with leading researchers in the United States and Great Britain, performed a clinical trial that has successfully demonstrated the efficacy of gene therapy in the treatment of LCA.  LCA is caused by a mutation in the RPE65 gene.  In this clinical trial, a normal RPE65 gene was injected into the retina to replace the damaged gene and renew protein production. Participants Dana and Yossi were treated with this gene therapy in just part of the retina of one eye, with dramatic results. Shortly after treatment, both participants noted a substantial improvement in their vision.

When asked about the results of this treatment, Yossi said, "I felt the real change, the real revolution, after 21 days. It was amazing because today I see things that I have never seen before. I'm very proud to be a part of this research." Dana said, "Learning of new treatment was a life-changing event. I'm experiencing a real change. I was surprised to see real improvement in my vision."

Yossi and Dana's self-reporting of visual improvement is corroborated by objective, quantitative measurements of the treated area that also show significant improvement. With the continuation of this research, these scientists will be able to develop gene therapy to treat additional retinal degeneration diseases and make it possible to treat many more patients.

To watch a just-released video with more information about this clinical trial, its researchers and study participants, please visit http://www.mvrf.org/news.php.

Dr. Banin says: "You cannot imagine what an effect this has had not only on the treated patients, their families and on us, but also on the wider population of patients with retinal and macular degenerations here in Israel, who suddenly feel some glimmer of hope.."

Keith A. Lampman, Executive Director of MVRF, says, "We are extremely excited about the results of this study and feel confident that, in close collaboration with our partners across the globe, we are closer than ever to a cure for retinal diseases."

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First patient receives novel gene therapy for a type of blindness

The first patient to receive gene therapy for an incurable type of blindness was treated at the John Radcliffe Hospital in Oxford this week as part of a trial led by Oxford University.

If successful, the advance could lead to the first-ever treatment for choroideraemia, a progressive form of genetic blindness that first arises in childhood and is estimated to affect over 100,000 people worldwide.

‘This disease has been recognised as an incurable form of blindness since it was first described over a hundred years ago. I cannot describe the excitement in thinking that we have designed a genetic treatment that could potentially stop it in its tracks with one single injection,’ says Professor Robert MacLaren of the University of Oxford, who is leading the trial.

Jonathan Wyatt, 63, an arbitration lawyer from Bristol had the surgery at the Oxford Eye Hospital based at the John Radcliffe – the main NHS centre for this trial. He is the first of 12 people in this initial human trial that will receive the novel gene therapy. Mr Wyatt was diagnosed with choroideraemia in his late teens and has suffered progressive sight loss ever since. He now sees only blackness except for a small area of a few degrees in diameter in the centre of his vision.

Choroideraemia is a genetic disease that leads to progressive degeneration of the retina in the eye. It generally affects males only and there is no treatment. The diagnosis is usually made in childhood and leads to blindness in men by their forties. It occurs due to deficiency of the REP1 gene located on the X chromosome.

The novel gene treatment was developed by Professor MacLaren at Oxford University, in collaboration with Professor Miguel Seabra at Imperial College, London. It is designed to provide the gene missing in people with choroideraemia to stop the deterioration that gradually leads to blindness.

It uses a virus essentially as a delivery vehicle that ferries DNA including the missing gene into the right part of the eye. The virus has been engineered to infect the light-sensitive cells in the retina known as photoreceptors. There the gene is switched on and becomes active.

With this particular gene therapy, the treatment could provide a one-off permanent correction of the disease because the gene is thought to remain in the retinal cells indefinitely.

‘This trial represents the world’s first ever attempt to treat this disease and the first time that gene therapy has been directed towards the light-sensitive photoreceptor cells of the human retina,’ says Professor MacLaren. ‘This represents a major breakthrough and is highly significant for patients who are losing sight from other photoreceptor diseases, such as retinitis pigmentosa.’

The trial will see 12 patients undergo surgery in which the gene therapy is injected into one eye. The other eye would then act as a control against which to assess any treatment effect. The researchers would however aim to go on to treat the second eye, should the treatment be proven to be effective.

The aim of the trial is primarily to assess safety, but it will also gain initial data on how effective the treatment is. The researchers estimate that it will take two years to know whether or not the degeneration has been stopped completely by the gene therapy.

‘While safety appears so far to be fine, the efficacy of the gene therapy will only be evident after 24 months. We need this time to measure any effect as the degeneration caused by choroideraemia is slow,’ explains Professor MacLaren, who is also an honorary consultant at the Oxford Eye Hospital and Moorfields Eye Hospital.

The clinical trial is funded by a grant awarded to the University of Oxford by the Health Innovation Challenge Fund – a translational award scheme funded jointly by the Wellcome Trust and the Department of Health.

Professor Seabra, who played a key role at Imperial College London in identifying the gene causing choroideraemia and in eliciting the mechanism of cell death in the retina, comments: ‘The ability to offer a gene replacement treatment for these patients was the final objective of 20 years of intense research in my laboratory. This is a moment of fulfilment for us and a dream come true for all choroideraemia patients.’

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