Gene therapy for macular degeneration?

Gene therapy successfully treated a canine version of Best disease, a blinding disorder, the effects lasting more than five years. In these images of the retina of untreated (left) and treated (right) dogs, one can see that BEST1 gene expression (in red) was restored following treatment. In addition, the threrapy restored the structure of the RPE (green layer), a layer of cells that supports the light-sensing photoreceptor cells.

Researchers from the University of Pennsylvania have developed a gene therapy that successfully treats a form of macular degeneration in a canine model. The work sets the stage for translating the findings into a human therapy for an inherited disease that results in a progressive loss of central vision and which is currently untreatable.

The study, published this week in Proceedings of the National Academy of Sciences, was led by Karina E. Guziewicz, a research assistant professor in Penn’s School of Veterinary Medicine, and Artur V. Cideciyan, a research professor of ophthalmology in Penn’s Perelman School of Medicine. The research is part of a long-standing partnership between Penn Vet and Penn Medicine scientists to push forward gene and other novel therapies for blinding disorders.

Guziewicz.Eye pre- and post-treatment.

A view of a dog’s eye before (left) and 5 years after (right) the gene therapy underscores how the treatment reversed a sizeable lesion–and lasted. The black mark visible on the treated eye is the injection site.

“In the eye, you have these two integral retinal cell layers that puzzle into one another and, like a zipper, they interweave your vision cells and the support cells,” Cideciyan says. “What this disease is doing is basically unzipping those layers, and what we’ve done is rezip them, bringing them together tightly.”

“With this research,” Guziewicz says, “we have demonstrated that there is a therapy that is working in a large animal model. Following safety studies, a human clinical trial could be less than two years away.”

Guziewicz and Cideciyan’s colleagues who collaborated on the work included vision scientists from Penn Vet’s Division of Experimental Retinal Therapies, Gustavo D. Aguirre, professor of medical genetics and ophthalmology, and William Beltran, professor of ophthalmology; and from Penn Medicine Samuel G. Jacobson, professor of ophthalmology.

Best disease, or vitelliform macular degeneration, is an inherited blinding disorder caused by mutations in the BEST1 gene. It often manifests in children and young adults, gradually robbing them of their central vision.

Through a variety of studies during the last several years, the Penn team has shown that dogs, too, develop a strikingly similar disease. A 2014 study led by Beltran revealed that dogs, like humans, have a tiny region at the center of their retina that is densely packed with cone photoreceptor cells—those responsible for reading, driving, and perceiving fine details—called a fovea. BEST1 mutations in both humans and dogs compromise the fovea, leading to vision loss.

Based on success treating other blinding diseases, the group has been developing a gene therapy to treat this condition. And working with the canine model, Guziewicz and colleagues reported last year the discovery of the underlying defect responsible for disease, the failure of a supporting structure known as the retinal pigment epithelium, or RPE, to tightly connect to the light-sensing photoreceptor cells. That finding gave the researchers the outcome measures they needed to determine with confidence whether a gene therapy would work.

In the newly published study, the researchers further probed the canine Best disease while also examining human patients with BEST1 mutations to see if analogous defects could be seen.

Beltran-Aguirre-Guziewicz-Cideciyan-Jacobson

The Penn research team included William Beltran, Gustavo Aguirre and Karina Guziewicz of the School of Veterinary Medicine and Artur Cideciyan and Samuel Jacobson of the Perelman School of Medicine.

While Best disease and related conditions were known to affect central vision, it had long been known that the disorders involved dysfunctions all across the retina. Examining the retinas of dogs with disease mutations, the researchers found a retina-wide abnormality; the internal surface of the RPE, critical for communication with the light-sensing photoreceptor cells, failed to develop normally, preventing the photoreceptors from coming into close contact. This could be detected very early, when the affected dogs were only 6 weeks old.

“This was unexpected,” says Aguirre, “and helps explain this puzzling finding in the disease that, while patients have lesions that are very local, when you do electrophysiological measurements you see that there is a retina-wide defect. Now that we can see this separation happening very early between the RPE and photoreceptors, we know that the disease involves a structural abnormality across the retina that precedes the loss of photoreceptor cells.”

An additional finding that arose when the dogs were examined under light was that light exposure dramatically increased the severity of the RPE-photoreceptor separation. When dogs were returned to darkness, the separation decreased.

It’s unknown whether this association with light is present in human patients. But the researchers did take steps to show that a similar separation between RPE and photoreceptors is affecting vision. By measuring the time it took for patients to adjust to darkness, or acquire “night vision,” the researchers obtained a proxy for the time it takes for nutrients to diffuse between these two layers of cells, a process that enables dark adaptation. They showed that a longer distance was associated with much slower rates of nutrient transport.

“This flow of nutrients normally occurs over a very small distance,” Cideciyan says. “So if you have a separation between these two layers, the recovery rate to get night vision slows down. The implication is that, if we could correct the apposition of these two tissues, we would correct the visual defect as well.”

That is what the researchers set out to do in testing the gene therapy construct. Using a harmless viral vector, they injected a healthy copy of the BEST1 gene, using either the canine or human version of the gene, into the dogs with the canine version of Best disease, at early- and middle-disease stages.

Remarkably, they were able to correct both mild and more severe lesions. Close examination of the eyes of treated dogs revealed that the gene therapy restored the “zipper” structure between RPE and photoreceptor cells. To ensure their therapy was functioning to correct this RPE-photoreceptor interface, they exposed to light the eyes of dogs that had been previously injected with gene therapy and saw that the triggered RPE-photoreceptor cell separation did not occur in the area of the retinas that had been treated.

“Since we understand the mechanism of disease better than before,” says Guziewicz, “it also allows us to understand the mechanism of rescue. We can visualize these projections extending from the RPE that never existed before; it’s incredible. That restored the proper apposition between those two cell layers.”

The therapy appears to be lasting, as the treated dogs’ eyes remained disease-free for as long as five years.

Work remains to be done before embarking on human clinical trials, including identifying which patients might benefit, assessing how far advanced a disease could be and still be effectively treated, and ensuring safety so as not to compromise vision that the patients still have. But, given the closeness with which dogs recapitulate the human disease, the researchers are hopeful that the findings will translate.

“On a human level, there are a lot of families who know that previous generations have had this disease, and the young people can live in fear of whether it is going to affect them,” Jacobson says. “This is the unveiling of a mechanism and a treatment for a previously untreatable form of juvenile or inherited macular degeneration, and that’s a major step forward.”

Learn more: New Gene Therapy Corrects a Form of Inherited Macular Degeneration in Canine Model

 

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Restoring normal blood glucose levels in mice with type 1 diabetes using gene therapy

In these two microscopy images, human islets (the source of insulin cells) were poisoned with a drug to remove the insulin cells, and then treated with either an empty virus (left panel) or the therapeutic virus (right panel), and then grown in a diabetic mouse. The green staining on the right reflects abundant insulin cell in these islets. The blood sugar of the diabetic mice were made normal by the gene-therapy-treated human islets on the right.
CREDIT
George Gittes and Xiangwei Xiao

Type 1 diabetes is a chronic disease in which the immune system attacks and destroys insulin-producing beta cells in the pancreas, resulting in high blood levels of glucose. A study published January 4th in Cell Stem Cell demonstrates that a gene therapy approach can lead to the long-term survival of functional beta cells as well as normal blood glucose levels for an extended period of time in mice with diabetes. The researchers used an adeno-associated viral (AAV) vector to deliver to the mouse pancreas two proteins, Pdx1 and MafA, which reprogrammed plentiful alpha cells into functional, insulin-producing beta cells.

“This study is essentially the first description of a clinically translatable, simple single intervention in autoimmune diabetes that leads to normal blood sugars, and importantly with no immunosuppression,” says senior study author George Gittes of the University of Pittsburgh School of Medicine. “A clinical trial in both type 1 and type 2 diabetics in the immediate foreseeable future is quite realistic, given the impressive nature of the reversal of the diabetes, along with the feasibility in patients to do AAV gene therapy.”

Approximately 9% of the world’s adult population has diabetes, which can cause serious health problems such as heart disease, nerve damage, eye problems, and kidney disease. One fundamental goal of diabetes treatment is to preserve and restore functional beta cells, thereby replenishing levels of a hormone called insulin, which moves blood glucose into cells to fuel their energy needs. But in patients with type 1 diabetes, beta-cell replacement therapy is likely doomed to failure because the new cells might fall victim to the same autoimmunity that destroyed the original cells.

A potential solution to this problem is to reprogram other cell types into functional beta-like cells, which can produce insulin but are distinct from beta cells and therefore are not recognized or attacked by the immune system. To explore the feasibility of this approach, Gittes and first author Xiangwei Xiao of the University of Pittsburgh School of Medicine engineered an AAV vector to deliver to the mouse pancreas proteins called Pdx1 and MafA, which support beta cell maturation, proliferation, and function. The goal was to generate functional beta-like cells from pancreatic alpha cells, which may be the ideal source for beta cell replacement. For example, alpha cells are plentiful, resemble beta cells, and are in the correct location, all of which could facilitate reprogramming.

By comparing the gene expression patterns of normal beta cells and insulin-producing cells derived from alpha cells, the researchers confirmed nearly complete cellular reprogramming. This gene therapy approach restored normal blood glucose levels in diabetic mice for an extended period of time, typically around four months, and the new insulin-producing cells derived almost exclusively from alpha cells. Moreover, the strategy successfully generated functional insulin-producing cells from human alpha cells.

“The viral gene therapy appears to create these new insulin-producing cells that are relatively resistant to an autoimmune attack,” Gittes says. “This resistance appears to be due to the fact that these new cells are slightly different from normal insulin cells, but not so different that they do not function well.”

Several features of this approach could facilitate translation to humans. For one, AAV vectors like those used in this study are currently undergoing various gene therapy trials in humans. Moreover, the viral vectors can be delivered directly to the human pancreas through a routinely performed non-surgical endoscopic procedure; however, this procedure can elicit pancreatic inflammation. In addition, no immunosuppression is required, so patients would avoid related side effects such as an increased risk of infection.

However, one major concern was that the mice did eventually return to the diabetic state, suggesting that this treatment would not represent a definitive cure for the disease. “The protection from recurrent diabetes in the mice was not permanent, although some studies would suggest that processes in mice are highly accelerated, so four months in mice might translate to several years in humans,” Gittes says.

Currently, the researchers are testing their approach in primates. “If we are able to show efficacy in non-human primates, we will begin work with the FDA to get approval for the use of this viral gene therapy in diabetic patients, both type 1 and type 2,” Gittes says.

Learn more: Gene therapy restores normal blood glucose levels in mice with type 1 diabetes

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Could gene therapy provide long-term protection against HIV?

Credit: NIAID/Flickr
HIV-infected T cell

FINDINGS

Through gene therapy, researchers engineered blood-forming stem cells (hematopoietic stem/progenitor cells, or HSPCs) to carry chimeric antigen receptor (CAR) genes to make cells that can detect and destroy HIV-infected cells. These engineered cells not only destroyed the infected cells, they persisted for more than two years, suggesting the potential to create long-term immunity from the virus that causes AIDS.

BACKGROUND

Antiviral drugs can suppress the amount of HIV in the body to nearly undetectable levels, but only an effective immune response can eradicate the virus. Researchers have been seeking a way to improve the body’s ability to combat the virus by engineering blood-forming stem cells to specifically target and kill HIV-infected cells for the life of the individual. Although chimeric antigen receptor (CAR) T-cells have emerged as a powerful immunotherapy for various forms of cancer – and show promise in treating HIV-1 infection – the   therapy may not impart long-lasting immunity. Researchers, physicians and patients need T cell-based products that can respond to malignant or infected cells that may reappear months or years after treatment.

METHOD

Because HIV uses CD4 to infect cells, the researchers used a CAR molecule that hijacks the essential interaction between HIV and the cell surface molecule CD4 to make stem cell-derived T-cells target infected cells.  When the CD4 on the CAR molecule binds to HIV, other regions of the CAR molecule signal the cell to become activated and kill the HIV infected cell.  The researchers found that, in test animals, modification of the blood-forming stem cells resulted in more than two years of stable production of CAR-expressing cells without any adverse effects. In addition, these cells were widely distributed throughout the lymphoid tissues and gastrointestinal tract, which are major anatomic sites for HIV replication and persistence in infected people. Most important, engineered CAR T-cells showed efficacy in attacking and killing HIV-infected cells.

IMPACT

These findings are the first to show that blood-forming stem cells can be modified with a CAR therapy that can safely engraft in the bone marrow, mature and become functional immune cells throughout the body. This could lead to the development of an approach allowing for safe, lifelong immunity to HIV. Such an approach is likely to work best when performed in combination with other treatment strategies, such as antiretroviral therapy.  Researchers hope that this type of therapy could reduce infected individuals’ dependence on antiviral medications, lower the cost of therapy, and permit the possible eradication of HIV from its hiding places in the body. The approach also has potential against other infections or malignancies.

Learn more: Gene Therapy Using CAR T-Cells Could Provide Long-Term Protection Against HIV

 

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Gene therapy to provide a cure for haemophilia?

Jake Omer and family

A ‘cure’ for haemophilia is one step closer, following results of a groundbreaking gene therapy trial led by the NHS in London.

Clinical researchers at Barts Health NHS Trust and Queen Mary University of London have found that over one year on from a single treatment with a gene therapy drug, participants with haemophilia A (the most common type) are showing normal levels of the previously missing protein, and effectively curing them.

A single infusion of the gene therapy drug showed improved levels of the essential blood clotting protein Factor VIII, with 85 per cent of patients achieving normal or near-normal Factor VIII levels even many months after treatment.

The ‘transformational’ results have particular significance as the first successful gene therapy trial for the haemophilia A.

A hereditary genetic condition

There are around 2000 people with severe haemophilia A in the UK. A hereditary genetic condition dominantly affecting men, people with severe haemophilia A have virtually none of the protein factor VIII which is essential for blood to clot. It puts those affected at risk of excessive bleeding even from the slightest injury as well as causing spontaneous internal bleeding, which can be life-threatening. Recurring bleeding into joints can also lead to progressive joint damage and arthritis. The only current treatment involves multiple weekly injections to control and prevent bleeding, but there is no cure.

The trial saw patients across England injected with a copy of the missing gene, which allows their cells to produce the missing clotting factor. Following patients for up to nineteen months, tests show that eleven out of thirteen patients in the trial now have normal or near normal levels of the previously missing factor and all thirteen patients have been able to stop their previously regular treatment.

Professor John Pasi, Haemophilia Centre Director at Barts Health NHS Trust and Professor of Haemostasis and Thrombosis at Queen Mary University of London explained: “We have seen mind-blowing results which have far exceeded our expectations. When we started out we thought it would be a huge achievement to show a five per cent improvement, so to actually be seeing normal or near normal factor levels with dramatic reduction in bleeding is quite simply amazing. We really now have the potential to transform care for people with haemophilia using a single treatment for people who at the moment must inject themselves as often as every other day. It is so exciting.”

The team will now hold further tests widening participants globally to include people in the USA, Europe, Africa and South America.

Professor Pasi continued: “Incredibly exciting is the potential for a significant change in how haemophilia is treated globally. A single dose of medication that can so dramatically improve the lives of patients across the world is an amazing prospect.”

Professor Jo Martin, President, The Royal College of Pathologists said: “Pathology research is often responsible for ground-breaking developments in diagnoses and treatments that transform the lives of patients.

“What is truly remarkable about this revolutionary new gene therapy are the profound life-changing effects it offers patients with haemophilia. We would like to congratulate College fellow, Professor Pasi, and his team at Barts Health NHS Trust and Queen Mary University of London for their work in creating a simple but transformational treatment for patients.”

Case study

Jake Omer, 29 lives in Billericay and is married with two children, aged 3 years and a baby of 5 weeks. Diagnosed at two years old, he has had frequent injections of factor VIII to prevent bleeds ever since. Before he was treated with the gene therapy, Jake would wake up early before work to inject three times a week as well as injecting whenever he had an injury to stop the bleeding. As a result of of repeated bleeding Jake has arthritis in his ankles. His father is a Turk-Cypriot and as a child he and his family could never travel to visit relatives in case he needed medical care as the facilities wouldn’t have been available.

Jake said: “The gene therapy has changed my life. I now have hope for my future. It is incredible to now hope that I can play with my kids, kick a ball around and climb trees well into my kids’ teenage years and beyond. The arthritis in my ankles meant I used to worry how far I would be able to walk once I turned 40. At 23 I struggled to run 100m to catch a bus; now at 29 I’m walking two miles every day which I just couldn’t have done before having the gene therapy treatment.

“It’s really strange to not have to worry about bleeding or swellings. The first time I noticed a difference was about four months after the treatment when I dropped a weight in the gym, bashing my elbow really badly. I started to panic thinking this is going to be really bad, but after icing it that night I woke up and it looked normal. That was the moment I saw proof and knew that the gene therapy had worked.”

Learn more: Groundbreaking gene therapy trial set to cure haemophilia

 

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Gene therapy can restore vision to people with an inherited retinal disorder

via American Academy of Ophthalmology

Study shows first-of-its kind gene therapy can restore vision to people with an inherited retinal disorder

Patients who had lost their sight to an inherited retinal disease could see well enough to navigate a maze after being treated with a new gene therapy, according to research presented today at AAO 2017, the 121st Annual Meeting of the American Academy of Ophthalmology.

Patients in the study had a condition called Leber congenital amaurosis (LCA), which begins in infancy and progresses slowly, eventually causing complete blindness. This new, first-of-its kind gene therapy is currently under review by the U.S. Food and Drug Administration for potential approval this year. There are currently no treatments available for inherited retinal diseases.

Ophthalmologist Stephen R. Russell, M.D., of the University of Iowa, is one of the lead researchers for this pioneering treatment. Data from the first randomized, controlled, phase 3 study showed that 27 of 29 treated patients (93 percent) experienced meaningful improvements in their vision, enough that they could navigate a maze in low to moderate light. They also showed improvement in light sensitivity and peripheral vision, which are two visual deficits these patients experience.

Approval could open the door for other gene therapies that could eventually treat the more than 225 genetic mutations known to cause blindness. It could be applied to retinitis pigmentosa, another inherited retinal disease caused by a defective gene. Or in the future, gene therapy could possibly provide key proteins needed to restore vision in more common diseases such as age-related macular degeneration.

LCA is rare, affecting about 1 in 80,000 individuals. It can be caused by one or more of 19 different genes. The treatment, called voretigene neparvovec (Luxturna, Spark Therapeutics), involves a genetically modified version of a harmless virus. The virus is modified to carry a healthy version of the gene into the retina. Doctors inject billions of modified viruses into both of a patient’s eyes.

Treatment doesn’t restore normal vision. It does, however, allow patients to see shapes and light, allowing them to get around without a cane or a guide dog. It is unclear how long the treatment will last, but so far, most patients have maintained their vision for two years.

More than 200 patients with LCA have participated in gene therapy trials since 2007.

However, no gene therapy has gotten this close to FDA approval for retinal disease or any other eye disease. In October, an advisory committee to the FDA unanimously endorsed the treatment. The FDA isn’t obligated to follow the recommendations of its advisory committees, but it usually does. The agency is expected to make its decision no later than January 2018.

Learn more: Genetic Treatment for Blindness May Soon be Reality

 

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