Tag: research

Technology Transfer

Researchers Repair Faulty Brain Circuits Using Nanotechnology

Researchers Repair Faulty Brain Circuits Using Nanotechnology

Aug. 21, 2019

The following was originally published in Johns Hopkins Medicine’s Newsroom.

Working with mouse and human tissue, Johns Hopkins Medicine researchers report new evidence that a protein pumped out of some — but not all — populations of “helper” cells in the brain, called astrocytes, plays a specific role in directing the formation of connections among neurons needed for learning and forming new memories.

Using mice genetically engineered and bred with fewer such connections, the researchers conducted proof-of-concept experiments that show they could deliver corrective proteins via nanoparticles to replace the missing protein needed for “road repairs” on the defective neural highway.

Red 8.3 astrocytes in the spine of a mouse. (Courtesy of the Rothstein Lab.)

Since such connective networks are lost or damaged by neurodegenerative diseases such as Alzheimer’s or certain types of intellectual disability, such as Norrie disease, the researchers say their findings advance efforts to regrow and repair the networks and potentially restore normal brain function.The findings are described in the May issue of Nature NeuroscienceThe technology is available for licensing through Johns Hopkins Technology Ventures.

“We are looking at the fundamental biology of how astrocytes function, but perhaps have discovered a new target for someday intervening in neurodegenerative diseases with novel therapeutics,” says  Jeffrey Rothstein, M.D., Ph.D., the John W. Griffin Director of the Brain Science Institute and professor of neurology at the Johns Hopkins University School of Medicine.

“Although astrocytes appear to all look alike in the brain, we had an inkling that they might have specialized roles in the brain due to regional differences in the brain’s function and because of observed changes in certain diseases,” says Rothstein. “The hope is that learning to harness the individual differences in these distinct populations of astrocytes may allow us to direct brain development or even reverse the effects of certain brain conditions, and our current studies have advanced that hope.”

In the brain, astrocytes are the support cells that act as guides to direct new cells, promote chemical signaling, and clean up byproducts of brain cell metabolism.

Rothstein’s team focused on a particular astrocyte protein, glutamate transporter-1, which previous studies suggested was lost from astrocytes in certain parts of brains with neurodegenerative diseases. Like a biological vacuum cleaner, the protein normally sucks up the chemical “messenger” glutamate from the spaces between neurons after a message is sent to another cell, a step required to end the transmission and prevent toxic levels of glutamate from building up.

When these glutamate transporters disappear from certain parts of the brain –such as the motor cortex and spinal cord in people with amyotrophic lateral sclerosis (ALS) –glutamate hangs around much too long, sending messages that overexcite and kill the cells.

To figure out how the brain decides which cells need the glutamate transporters, Rothstein and colleagues focused on the region of DNA in front of the gene that typically controls the on-off switch needed to manufacture the protein. They genetically engineered mice to glow red in every cell where the gene is activated.

Normally, the glutamate transporter is turned on in all astrocytes. But, by using between 1,000- and 7,000-bit segments of DNA code from the on-off switch for glutamate, all the cells in the brain glowed red, including the neurons. It wasn’t until the researchers tried the largest sequence of an 8,300-bit DNA code from this location that the researchers began to see some selection in red cells. These red cells were all astrocytes but only in certain layers of the brain’s cortex in mice.

Because they could identify these “8.3 red astrocytes,” the researchers thought they might have a specific function different than other astrocytes in the brain. To find out more precisely what these 8.3 red astrocytes do in the brain, the researchers used a cell-sorting machine to separate the red astrocytes from the uncolored ones in mouse brain cortical tissue, and then identified which genes were turned on to much higher than usual levels in the red compared to the uncolored cell populations. The researchers found that the 8.3 red astrocytes turn on high levels of a gene that codes for a different protein known as Norrin.

Rothstein’s team took neurons from normal mouse brains, treated them with Norrin, and found that those neurons grew more of the “branches” — or extensions — used to transmit chemical messages among brain cells. Then, Rothstein says, the researchers looked at the brains of mice engineered to lack Norrin, and saw that these neurons had fewer branches than in healthy mice that made Norrin.

In another set of experiments, the research team took the DNA code for Norrin plus the 8,300 “location” DNA and assembled them into deliverable nanoparticles. When they injected the Norrin nanoparticles into the brains of mice engineered without Norrin, the neurons in these mice began to quickly grow many more branches, a process suggesting repair to neural networks. They repeated these experiments with human neurons too.

Rothstein notes that mutations in the Norrin protein that reduce levels of the protein in people cause Norrie disease — a rare, genetic disorder that can lead to blindness in infancy and intellectual disability. Because the researchers were able to grow new branches for communication, they believe it may one day be possible to use Norrin to treat some types of intellectual disabilities such as Norrie disease.

For their next steps, the researchers are investigating if Norrin can repair connections in the brains of animal models with neurodegenerative diseases, and in preparation for potential success, Miller and Rothstein have submitted a patent for Norrin.

Other authors of the publication are Sean Miller, Thomas Philips, Namho Kim, Raha Dastgheyb, Zhuoxun Chen, Yi-Chun Hsieh, J. Gavin Daigle,  Jeannie Chew, Svetlana Vidensky, Jacqueline Pham, Ethan Hughes, Michael Robinson, Rita Sattler, Jung Soo Suk, Dwight Bergles, Norman Haughey, Mikhail Pletnikov and Justin Hanes of Johns Hopkins, and Malika Datta and Raju Tomer of Columbia University.

This work was funded by grants from the National Science Foundation Graduate Fellowship Research Program and the National Institute of Neurological Disorders and Stroke (R01NS092067, R01NS094239).

Translational funding opportunity

Engineering Faculty’s Research on Retinal Cells, Brain Tumors Given…

Engineering Faculty’s Research on Retinal Cells, Brain Tumors
Given Boost with Cohen Fund Grants

July 29, 2019

Two faculty members from the Johns Hopkins Whiting School of Engineering have received grants for their research through the Cohen Translational Engineering Fund.

The fund, made possible by a generous commitment from Neil Cohen (class of 1983) and his wife, Sherry, serves as a catalyst for translating cutting-edge research into practice by providing faculty with critical early funding. The grant is designed to help researchers move their work out of the laboratory through assistance with tasks such as developing patents, obtaining materials and supplies and building prototypes.

Since its inception five years ago, the Cohen Fund has awarded more than $750,000 in grants for more than 20 projects.

During the most recent grant cycle, an outside panel of independent researchers and investors, innovation executives and venture investors heard presentations from five applicants in May at the 1812 Ashland building. Benjamin Gibson of Johns Hopkins Technology Ventures, who oversees the grant process, said the applications represented the diverse interests and technical strengths of Whiting faculty.

“The Cohen Fund Advisory Board meeting represents an excellent opportunity to bring WSE faculty together with experienced business professionals to showcase their strengths and provide valuable feedback regarding the commercialization of their technologies,” says Gibson, manager of JHTV’s Commercialization Strategy Group.

The winners will meet with JHTV staff at the end of the project and create a one-page marketing summary for their work.

Check JHTV’s website for when the next round of requests for proposals opens for the Cohen Fund.

Jin Kang

Fiber Optic Distal Sensor Controlled Drug Injector

Principal investigator: Jin Kang, Jacob Suter Jammer Professor of Electrical and Computer Engineering, Whiting School of Engineering

The pitch: A compact robotic tool that improves the safety and effectiveness of one of the most delicate surgeries.

Retinal diseases are the leading cause of childhood blindness worldwide and among the leading causes of vision loss in the United States. Treatments for the diseases are being developed, but they require the precise delivery of genes and stem cells to a specific layer of retinal tissue. Kang, who is internationally known for his work with fiber optic sensors and devices, is developing a handheld microinjector for transplanting retinal cells directly into the correct retinal layer. The tool uses advanced optical coherence tomography technology that allows surgeons to see transparent tissues more easily, maintain safe surgical positions and assess the depth of the microinjector’s penetration on a micron level.

Johns Hopkins Technology Ventures helped Kang obtain patent protection for the technology, which is available for licensing through JHTV. Kang also founded a company, LIV Medtech Inc., through FastForward to develop the microinjector and other, similar tools.

MRI-Compatible Functional Cranial Implant for Pump-Assisted Chronic and Direct Medicine Delivery to Treat Neurologic Pathology

Chad Gordon

Principal investigators: Mehran Armand, director, Biomechanical and Image-Guided Surgical Systems (BIGSS), Whiting School of Engineering, and Chad Gordon, director, neuroplastic and reconstructive surgery, Johns Hopkins University School of Medicine

The pitch: A novel way to treat a deadly brain tumor.

Each year, 18,000 patients in the United States are diagnosed with glioblastoma multiforme (GBM) brain tumors and live on average just another 14 months. The tumors have a 90% recurrence rate after initial treatment, and their rapid growth makes removal impossible and radiation difficult without damaging surrounding healthy tissue. Armand, Gordon and their team have developed a therapeutic delivery system embedded in a patient’s own skull or synthetic implant, allowing both chronic and direct medicine delivery to treat GBM. The MRI-compatible device sits between the scalp and brain to optimize safety and minimize visual deformity. In the future, the device could be used to treat any other chronic intracranial neuropathology and could be adapted for patient-specific dosage or timing of release.

JHTV has pursued patent protection for the technology, which is available for licensing. The researchers have consulted several neurotechnology/cranial implant manufacturers, including Longeviti Neuro Solutions, a FastForward startup.

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