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Insulin cells determine weight-loss surgery success rate The ability to produce insulin is pivotal to the success of weight-loss surgery in patients with type 2 diabetes, scientists have found. Their study provides a better point of departure for advice and determining which patients will benefit from surgery

New gene therapy for vision loss from a mitochondrial disease

NIH-funded study shows success in targeting mitochondrial DNA in mice

Researchers funded by the National Institutes of Health have developed a novel mouse model for the vision disorder Leber hereditary optic neuropathy (LHON), and found that they can use gene therapy to improve visual function in the mice. LHON is one of many diseases tied to gene mutations that damage the tiny energy factories that power our cells, called mitochondria.

Dr. John Guy and colleagues added a homing signal to a virus in order to deliver the ND4 gene into mitochondria. A marker for the gene is shown in red and the ND4 protein is shown in green, inside retinal ganglion cells in the mouse eye. The nuclei of retinal ganglion cells are shown in blue. Credit: Dr. Hong Yu, Bascom Palmer.

“This study marks an important contribution to research on LHON, and in efforts toward an effective therapy. But the implications are even broader, because the approaches that the investigators used could aid therapy development for a vast array of other mitochondrial diseases,” said Maryann Redford, D.D.S, M.P.H., a program director in Collaborative Clinical Research at NIH’s National Eye Institute, which helped fund the study.

Mitochondria are as complex as any modern manufacturing facility, with specialized machinery for converting nutrients and oxygen into cellular energy. They even have their own DNA, and it is mutations within this mitochondrial DNA (mtDNA) that lead to LHON, as well as a host of other diseases. But the unique nature of mtDNA has presented challenges for developing and testing potential therapies for such diseases.

Until now, “there was no efficient way to get DNA into mitochondria,” said John Guy, M.D., professor of ophthalmology and director of the ocular gene therapy laboratory at the Bascom Palmer Eye Institute, University of Miami Miller School of Medicine. Dr. Guy’s laboratory is among the first to develop an approach that can target mtDNA in living mice and people.

Their success in creating a mouse model of LHON and using it to test an investigational gene therapy is described today in the Proceedings of the National Academy of Sciences.

The global impact of LHON is unknown. In England, the estimated prevalence is about 1 in 30,000. Early symptoms include blurry vison and usually appear during the teens or early twenties. Eyesight tends to worsen over time, eventually leading to a severe loss of sharpness (acuity) and color vision. These problems are caused by a loss of retinal ganglion cells — the cells that carry visual signals from the retina through the optic nerve and into the brain.

The most common mutation behind LHON impairs a mitochondrial gene called ND4. Dr. Guy began to research a possible gene therapy approach for delivering a substitute copy of the gene into mitochondria about 15 years ago. In most studies and applications of gene therapy, viruses have become the preferred vessel for delivering genes into cells. But viruses evolved to invade the body’s cells and penetrate the nucleus, which contains the bulk of our DNA, comprising about 20,000 genes. Most viruses are poor at penetrating mitochondria.

To fix that, Dr. Guy and his team took advantage of the fact that mitochondria import cellular proteins that they cannot make themselves. By attaching a bit of one such protein to the outer shell of a virus — called an adeno-associated virus — he effectively gave the virus a homing signal and entry code into mitochondria.

This modified virus has been the key to creating a mouse that replicates LHON and to an investigational gene therapy for LHON that is currently in clinical trials.

To create a mouse model for LHON, the researchers loaded the virus with a defective copy of the ND4 gene carrying the same mutation that causes about 70 percent of LHON cases. They also included DNA coding for a red fluorescent protein, as a visible marker for the virus and its payload. Then they injected the virus into fertilized mouse egg cells, and grew the cells to maturity.

After breeding the mice through several generations, the researchers had their mouse model. The presence of the virally encoded ND4 mutation in the eye was confirmed by essentially doing an eye exam to look for the red fluorescent marker. Over time, the mice showed a loss of retinal ganglion cells, atrophy (shrinkage) of the optic nerve, and a decline in visual responses, as seen in a type of electrical recording from the retina known as an electroretinogram.

To develop a gene therapy for LHON, the team packaged the normal human ND4 gene into the same stealthy virus. This combination, when injected into the eye, led to improved visual function in the LHON mouse model. When injected into normal mice, the virus carrying ND4 did not cause any adverse effects on vision.

Prior to development of the new mouse model, Dr. Guy’s lab had shown that they could produce temporary signs of LHON in mice. They were able to prevent development of LHON in the mice, but not reverse it. “Now we’ve shown that we can improve visual function after it’s been lost,” he said.

The mouse research is helping inform an ongoing NEI-supported clinical trial, which is led by Dr. Guy and is testing the safety of the same gene therapy approach (without the red fluorescent protein) in people with LHON. The trial is recruiting LHON patients who fit into three categories — those with chronic vision loss in both eyes, with recent-onset vision loss in both eyes, or with recent-onset vision loss in one eye but no signs of abnormal vision in the other eye. For more information, visit http://www.clinicaltrials.gov and search for the trial identifier NCT02161380.

Health Research:Improving gene therapy ♦ Depressive ruminations and the idling brain ♦ Pharmacists help patients with hypertension

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Pharmacists help patients with hypertension Patients with hypertension benefit from interacting with a medical team that includes a pharmacist. Two studies showed pharmacist-included care teams delivered more hands-on and tailored medication regimens to patients, which yielded more effective blood-pressure control results than for those patients who did not have a pharmacist on hand.

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Treating ships' ballast water: Filtration preferable to disinfection Untreated ballast water discharge from ships can spread living organisms and even pathogens across the world thereby introducing non-native or invasive species into the local environment. Scientists therefore recommend using physical treatment processes such as filtration rather than electrochemical disinfection, which creates countless potentially toxic compounds.

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Critical genes responsible for brain tumor growth identified After generating new brain tumor models, scientists have identified the role of a family of genes underlying tumor growth in a wide spectrum of high grade brain tumors.

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Study advances potential of tumor genome sequencing and DNA-based blood tests in precision treatment In a genome-sequencing study of pancreatic cancers and blood in 101 patients, scientists say they found at least one-third of the patients' tumors have genetic mutations that may someday help guide precision therapy of their disease. Results of blood tests to detect DNA shed from tumors, they say, also predicted cancer recurrence more than half a year earlier than standard imaging methods.

License for cutting: How intracellular signaling regulates growth factor production Cancer cells need life-essential molecules to proliferate. These so-called growth factors are activated by ectodomain shedding of precursor proteins on the outside of the plasma membrane, mainly carried out by three human cleavage enzymes. A pharmaceutical blocking of these enzymes could hinder cancer from growing but would also inhibit other life-essential processes. Now, researchers have shown that the factor-precursor-producing cells themselves determine if and when cleavage may occur. This is decided by intracellular signaling. Interfering with defined signaling in cells producing cancer growth factors could be developed into a new way of cancer treatment.

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Gene therapy restores hearing in deaf mice Using gene therapy, researchers have restored hearing in mice with a genetic form of deafness. More than 70 different genes are known to cause deafness when mutated. The scientists focused on a gene called TMC1 because it is a common cause of genetic deafness, accounting for 4 to 8 percent of cases, and encodes a protein that plays a central role in hearing, helping convert sound into electrical signals that travel to the brain.

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Gene Therapy for Eye Disease Shows Benefits and Limitations

When you watch a sunset, an intricate series of events takes place in your eyes. Light passes through the front part of the eye and is refracted and focused on the retina, a thin, delicate tissue at the back of the eyes. The retina contains photoreceptor cells that detect light and convert it into electrical signals that are sent to the brain.

LCA is an inherited disorder that causes vision loss in childhood. It primarily affects the retina, the light-sensitive tissue at the back of the eye, as seen in this retinal photo. Credit: National Eye Institute.

The photoreceptor cells rely on a protein called RPE65 to recharge their light sensitivity and for long-term survival. About 10% of people with Leber congenital amaurosis (LCA), an inherited disorder that causes vision loss starting in childhood, have an altered form of the gene RPE65. Since LCA is caused by a faulty gene, scientists reasoned that they might be able to treat people by inserting a healthy gene. This strategy, in which genes are used to treat or prevent a disease, is known as gene therapy.

Clinical trials of experimental gene therapy for LCA and other diseases that affect the retina have been progressing for several years. One study supported by NIH’s National Eye Institute is being conducted by a team that includes Drs. Samuel G. Jacobson and Artur V. Cideciyan from the University of Pennsylvania, and Dr. William W. Hauswirth from the University of Florida, Gainesville.

The group treated 15 people who have LCA with retinal injections of a harmless virus engineered to carry normal RPE65 genes. As reported previously, participants who received the gene therapy injections were able to see dim lights that they weren’t able to see before treatment. This finding indicated that the newly introduced RPE65 gene was functional and was increasing the light sensitivity of the retina. The researchers determined that 4 of the 15 participants started relying on an area of the retina near the gene therapy injection site for seeing letters.

The participants routinely underwent extensive tests of their vision and imaging of the retina for up to 6 years after treatment. Follow-up results, reported in early 2013, found that while gene therapy improved vision for at least 3 years, photoreceptor cells continued to degenerate. Additional imaging results for 3 of the treated participants were published on May 14, 2015, in New England Journal of Medicine. Using sophisticated imaging capture and analysis techniques, the scientists were able to map the area of retinal improvement and track changes with time.

The team found that gene therapy improved patients’ eyesight and the sensitivity of the retina within a month of treatment. This was followed by a slow expansion of the area of improvement for up to 3 years after treatment. The area of improvement, however, then underwent a contraction.

The researchers determined that the RPE65 gene therapy boosted the photoreceptor cell recharge cycle, but didn’t delay cell death. The cells continued to die at the same rate as they do in the natural course of the disease, regardless of treatment.

Another study in the same journal—by researchers at Moorfields Eye Hospital and University College London—found that retinal sensitivity improved in 12 LCA patients treated with gene therapy, but then diminished after 12 months.

“Gene therapy for LCA demonstrated we could improve vision in previously untreatable and incurable retinal conditions,” Jacobson says. “Even though the current version of the therapy doesn’t appear to be the permanent treatment we were hoping for, the gain in knowledge about the time course of efficacy is an opportunity to improve the therapy so that the restored vision can be sustained for longer durations in patients.”

Study points way forward for retinal disease gene therapy

Gene therapy for Leber congenital amaurosis (LCA), an inherited disorder that causes vision loss starting in childhood, improved patients’ eyesight and the sensitivity of the retina within weeks of treatment. Both of these benefits, however, peaked one to three years after treatment and then diminished, according to results from an ongoing clinical trial funded by the National Eye Institute (NEI), part of the National Institutes of Health.

The results published online today in the New England Journal of Medicine focus on a subset of trial participants who routinely underwent extensive tests of their vision and imaging of the retina from baseline up to six years after treatment. These in-depth examinations revealed that the areas of treated retina rapidly gained visual sensitivity, expanded and then contracted.

“Gene therapy for LCA demonstrated we could improve vision in previously untreatable and incurable retinal conditions,” said Samuel G. Jacobson, M.D., Ph.D., who led the clinical trial at the University of Pennsylvania’s Scheie Eye Institute, Philadelphia. “Even though the current version of the therapy doesn’t appear to be the permanent treatment we were hoping for, the gain in knowledge about the time course of efficacy is an opportunity to improve the therapy so that the restored vision can be sustained for longer durations in patients.”

LCA is an inherited disorder that causes vision loss in childhood. It primarily affects the functioning of the retina, the light-sensitive tissue at the back of the eye, as shown here. Photo credit: National Eye Institute

The results contribute to the bigger picture of the potential benefits — and remaining problems to solve — in the field of gene therapy for LCA and other diseases that affect the retina, the light-sensitive tissue in the eye.

About 10 percent of people with LCA carry a mutated form of the gene RPE65, which makes a key protein found in the retinal pigment epithelium, a layer of cells that nourish the light sensors or photoreceptor cells of the retina. The RPE65 protein is critical for vision. In the retina, millions of photoreceptors detect light and convert it into electrical signals that are ultimately sent to the brain. Photoreceptors rely on the RPE65-driven visual cycle to recharge their light sensitivity. They also need RPE65 for their long-term survival. In LCA, the cells eventually die, muting eye-to-brain communication.

Dr. Jacobson along with Artur V. Cideciyan, Ph.D., University of Pennsylvania, and William W. Hauswirth, Ph.D., University of Florida, Gainesville, began the trial in 2007. Fifteen people with LCA received retinal injections of a harmless virus engineered to carry healthy RPE65 genes. This gene therapy relies on viral vectors as a means to deliver instructions for making the desired protein. In this case, the virus was designed to produce healthy RPE65. Dr. Hauswirth led the group that designed and produced the virus-gene material for testing in patients.

“Within days of the injections, some patients reported increases in their ability to see dim lights they had never seen before. It was remarkable for us to get this feedback that things were indeed changing positively,” said Dr. Jacobson.

In addition to the rapid onset of greater light sensitivity, the researchers discovered changes to another component of vision that occurred slowly.  Four of the 15 patients started relying on an area of the retina near the gene therapy injection site for seeing letters. Normally, the fovea with its high density of photoreceptors is responsible for seeing fine details.

“For some patients, preferential use of the treated area for seeing letters came about spontaneously about a year after the gene therapy and remained functional for up to six years,” said Dr. Cideciyan, who reported these findings in Investigative Ophthalmology & Visual Science in January.

For the current study, Dr. Jacobson’s team also examined the relationship between structure and function in the retina. Importantly, these results showed that photoreceptors continued to die at the same rate as they do in the natural course of the disease, regardless of treatment. The researchers concluded that gene therapy with RPE65 boosted the visual cycle, but did not delay photoreceptor cell death. Hence, the short-term gains in visual function.

“We now have six years of data showing that a gene therapy approach is safe and that it successfully improves vision in people with this blinding disease,” said Paul A. Sieving, M.D., Ph.D., director of NEI. “As with any application of a novel therapy, it now needs to be fine-tuned. More research is needed to understand the underlying biology and how we can preserve or restore photoreceptors for a lifetime. Restoring vision is at the heart of the NEI’s Audacious Goals Initiative, an effort to strategically fund research aimed at developing the knowledge and technology to make this goal a reality.”

Dr. Jacobson’s latest results are consistent with another independent investigation performed at Moorfields Eye Hospital and University College London. Those investigators found that retinal sensitivity improved in their LCA patients treated with gene therapy, but then it diminished after 12 months.  

The current findings suggest a number of potential strategies for improving the outcome of gene therapy, Dr. Jacobson said. For example, the ability to stage the disease prior to gene therapy would help clarify the potential benefits for each individual. The treatment could then be guided to retinal areas that contain enough functional photoreceptors to respond. Select patients may benefit from a second round of gene therapy, or from having an adjacent area of the retina treated, or from combining gene therapy with medications designed to boost the visual cycle or to protect the retina from cell loss.

“We've been able to positively alter and extend the visual life of patients with LCA, and we now have to develop workable strategies for extending it even further,” Dr. Jacobson said.

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