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Johns Hopkins Medicine scientists report the successful use of nanoparticles to deliver gene therapy for blinding eye diseases in rats and mice.

The research, described in the July 3, 2020, issue of Science Advances, provides evidence of the potential value of nanoparticle-delivered gene therapy to treat wet age-related macular degeneration — an eye disorder characterized by abnormal blood vessel growth that damages the light-sensitive tissue in the back of the eye — as well as rarer inherited blinding diseases of the retina.

Many gene therapy approaches depend on viral vectors, which use a virus’s natural ability to carry genetic material into cells. However, viruses create an immune response that prevents repeat dosing, and the most commonly used virus for ocular gene therapy cannot carry large genes.

“Some of the most prevalent inherited retinal degenerations are due to mutations in large genes that simply cannot fit into the most commonly used viral vector,” says study senior author Peter Campochiaro, M.D., the George S. and Dolores D. Eccles Professor of Ophthalmology at the Johns Hopkins University School of Medicine, and a retina specialist at the Johns Hopkins Medicine Wilmer Eye Institute. 

To overcome such limitations, Campochiaro and his colleagues developed a new approach involving a biodegradable polymer that surrounds and compacts long stretches of DNA, creating nanoparticles that can enter the cells. This technology allows the researchers to convert the cells of the eye into “minifactories” for a therapeutic protein.

In their rodent studies, the researchers showed that the genes delivered by nanoparticles stayed active within the cells for several months.

An estimated 1.6 million people in the United States with macular degeneration receive drug injections into the eye every four to six weeks to treat their disease. A gene therapy treatment could provide a way for the eye’s tissue to prevent further vision deterioration with only a few initial treatments. Genetic diseases that cause blindness could be treated in a similar way, by introducing functional versions of genes that inherited mutations have disabled.

“These results are extremely promising,” says study co-author Jordan Green, Ph.D., professor of biomedical engineering at the Johns Hopkins University School of Medicine. “We have the ability to reach the cells most significantly affected by degenerative eye disease with nonviral treatments that can allow the eye to create its own sustained therapies.”



Engineers at Johns Hopkins Medicine have solved the problem of distorted imaging scans that plague surgeons who need to use them to assess the placement of metal implants. They have developed a simple and practical solution to “steer” a scanner and direct its imaging beam so that most of the distortion problem is remedied.

Metal implants are commonly used to stabilize bones and structures in the body. During an operation, surgeons use a C-arm X-ray or CT (computed tomography) scanner to see if an implant is correctly positioned, has caused hemorrhaging or is impinging on adjacent nerves.

Problems with the implant can necessitate second surgeries that are expensive and often have poor outcomes, say the Johns Hopkins engineers.

“Metal artifacts are a giant headache for surgeons,” says Jeffrey Siewerdsen, Ph.D., professor of biomedical engineering at Johns Hopkins and leader of the team which published results of its proof-of-principle concept in the May 19, 2020, issue of the journal Physics in Medicine & Biology. “The beauty of the system we developed is that it has minimal change in the operating room workflow, time and cost.”

Metal transmits X-rays differently than tissue or bone, often yielding distortions, or artifacts, which appear on imaging scans. Artifacts may make the implant appear larger than real and form streaks throughout the image, blocking the surgeon’s ability to see potential problems.

Currently, scanners have built-in systems to analyze the X-ray signals and reduce the impact of metal artifacts. However, Siewerdsen says, these systems are not very effective, and the artifacts are worse with larger and denser implants.

“We steer the C-arm scan to give data that contain the fewest errors that could cause image artifacts,” says Siewerdsen. “In some cases, the solution is as simple as tilting the C-arm.”

Using cadavers, torso models and surgery simulations, Siewerdsen’s team developed a computer algorithm that assesses the location of a metal implant and determines the best position of the CT scanner to avoid artifacts. They dubbed the method “metal artifact avoidance,” since it avoids errors in the original data, unlike other techniques that try to correct them later.

The researchers found that their tests of the algorithm and tilting of the C-arm reduced the magnitude of errors in the X-ray data and resulting artifacts in the image. In one example, a 5-millimeter-diameter metal screw was implanted into the spine of a cadaver. Without the metal artifact avoidance algorithm, the image of the screw was distorted so that it appeared to be 8–12 millimeters in diameter. With the algorithm, the screw appeared as its real size.

“The key is to compute a scan orbit in a simple way that can be easily run by the C-arm,” says Siewerdsen. “We were surprised at how well it works.”

To enable the computer algorithm to work on most C-arms, manufacturers would need to calibrate their scanners to be tilted in the operating room, notes Siewerdsen. He adds that the metal artifact avoidance method can be paired with different algorithms that correct other kinds of artifacts.



Ensuring patients follow prescribed methods of care is a challenge for health care providers around the globe. In India, for example, 97% of HIV-infected pregnant women and their babies receive antiretroviral therapy (ART) for prevention of mother-to-child transmission (PMTCT). Poor outcomes persist, however, due to personal and socioeconomic factors — current estimates indicate that mother-to-infant transmission of HIV drops from 25% to less than 2% if HIV-infected women begin ART early in their pregnancy and maintain exclusive breastfeeding.

Researchers with the Johns Hopkins Center for Clinical Global Health Education (CCGHE) wanted to see if technology could assist uptake of PMTCT services. They supplied a group of HIV outreach workers (ORWs), who visited the homes of pregnant or breastfeeding women with specially designed videos — in the native language of the mothers — that were focused on (1) exclusive breastfeeding, (2) how to take ART medicines, (3) issues related to disclosure of HIV status and (4) ensuring HIV testing of babies. ORWs also collected information using smart forms on emocha Mobile Health’s platform and sent text alerts for upcoming and missed visits to mothers with HIV.

After two years, mothers and mothers-to-be who used technological aids showed significantly increased uptake of exclusive breastfeeding at two months as well as early infant diagnosis at six weeks compared to a control group, according to results published July 3, 2020, in the Journal of the International AIDS Society.

“Information given through videos in the local language to mothers with low health literacy in a standardized manner is a more effective way of communicating. Women in our study could relate to the women in the video stories,” says Nishi Suryavanshi, Ph.D., a CCGHE faculty member based in Pune, India, and the study’s lead author. “This kind of communication delivery is an easy and cost-effective method to encourage a positive change and improvement in patient behaviors, and to ensure consistent messaging is being delivered.”

While speaking with ORWs and their patients, the researchers found that the mobile health platform helped ORWs do their job more effectively, and that both ORWs and patients felt more confident and empowered to make decisions. The use of technology also can be scaled and optimized for all of India — or anywhere in the world — to change health-related behavior, according to Suryavanshi.

“An intervention could be adapted as per the cultural context of the setting,” she says. “For the United States, I think it could be adapted for lifestyle changes to reduce the risk of cardiovascular diseases, for example.”

The Johns Hopkins University has a financial interest in emocha, which was invented at the university. This financial interest includes equity in the company and entitlement to royalties. CCGHE founder Robert Bollinger Jr., M.D., M.P.H., a co-author of the paper, is an inventor of the technology who has equity and a royalty interest in emocha. He is a member of the emocha board of directors and a consultant for the company. These conflicts of interest are being managed by the university in accordance with its policies.



Johns Hopkins Medicine scientists have analyzed four versions of a protein made by the gene SYNGAP to find that one of the versions is the most promising target for developing therapies to correct the gene when it is mutated. The mutated form of the SYNGAP gene contributes to conditions including intellectual disability, autism and schizophrenia.

Among DNA in human cells, a portion of about 20,000 genes churn through the process of making proteins, the tiny molecules that keep cells in working order. Each gene is coded to produce a certain protein, but depending on the cell’s stage of development, environmental stress and other factors, a gene can produce different versions of its protein, called an isoform.

The function of one isoform compared with another could be as different as night and day, and scientists have long studied these variations. However, says Richard Huganir, Ph.D., professor of neuroscience and director of the Department of Neuroscience at the Johns Hopkins University School of Medicine, the functions of SYNGAP isoforms had not been well characterized, so he and his colleagues performed the analysis and published their results in the June 24, 2020, issue of eLife.

Huganir has been studying SYNGAP since he and his research team first isolated the gene in 1998. Studying the gene has been interesting, he says, because the protein it produces is a critical part of a neuron’s communications center.

SYNGAP is a protein that regulates the structure of the contact point between two neurons, called a synapse, where brain cells trade messages. Without SYNGAP, learning and memory are impaired. According to Huganir, mutations in the gene underlie 1% of intellectual disability, and SYNGAP is among the top five genes implicated in autism. He says that it also is genetically associated with schizophrenia.

To restore SYNGAP proteins, Huganir has been working with biotechnology companies on gene therapies that can boost their production. A key step is determining which of the protein’s four isoforms researchers should target.

Huganir’s team used mouse models to show that the SYNGAP alpha 1 isoform has the most potential for creating a gene therapy that increases SYNGAP protein production in a cell. The researchers found that SYNGAP alpha 1 has the strongest presence in the synapse in a state called liquid phase transition, during which the proteins are very well organized and defined. The other isoforms of SYNGAP, the researchers report, were not as potent as the alpha 1 version.

SYNGAP alpha 1 is typically produced in larger quantities shortly after birth, when synapses are forming and maturing in the brain. It’s a critical time for learning, says Huganir.

Journal Link: Science Advance, July-2020 Journal Link: Journal of Physics in Medicine & Biology, May-2020 Journal Link: Journal of the International AIDS Society, July-2020 Journal Link: eLife, June-2020