Nanoparticle Drug-Delivery To Treat Brain Disorders

In the past few decades, researchers have identified biological pathways leading to neurodegenerative diseases and developed promising molecular agents to target them. However, the translation of these findings into clinically approved treatments has progressed at a much slower rate, in part because of the challenges scientists face in delivering therapeutics across the blood-brain barrier (BBB) and into the brain.

To facilitate successful delivery of therapeutic agents to the brain, a team of bioengineers, physicians, and collaborators at Brigham and Women’s Hospital and Boston Children’s Hospital created a nanoparticle platform, which can facilitate therapeutically effective delivery of encapsulated agents in mice with a physically breached or intact BBB. In a mouse model of traumatic brain injury (TBI), they observed that the delivery system showed three times more accumulation in brain than conventional methods of delivery and was therapeutically effective as well, which could open possibilities for the treatment of numerous neurological disorders.

It’s very difficult to get both small and large molecule therapeutic agents delivered across the BBB,” said corresponding author Nitin Joshi, PhD, an associate bioengineer at the Center for Nanomedicine in the Brigham’s Department of Anesthesiology, Perioperative and Pain Medicine. “Our solution was to encapsulate therapeutic agents into biocompatible nanoparticles with precisely engineered surface properties that would enable their therapeutically effective transport into the brain, independent of the state of the BBB.”

The technology could enable physicians to treat secondary injuries associated with TBI that can lead to Alzheimer’s, Parkinson’s, and other neurodegenerative diseases, which can develop during ensuing months and years once the BBB has healed.

To be able to deliver agents across the BBB in the absence of inflammation has been somewhat of a holy grail in the field,” said co-senior author Jeff Karp, PhD, of the Brigham’s Department of Anesthesiology, Perioperative and Pain Medicine. “Our radically simple approach is applicable to many neurological disorders where delivery of therapeutic agents to the brain is desired.”

Findings were published in Science Advances.

https://www.eurekalert.org/

Eye Scanner Detects Molecular Aging in Humans

People often say that eyes are windows to the soul. Now it appears they may also be windows to human aging.  All people age, but individuals do so at different rates, some faster and others slower. While this observation is common knowledge, there is no universally accepted measure of biological aging. Numerous aging-related metrics have been proposed and tested, but no marker to date has been identified or noninvasive method developed that can accurately measure and track biological aging in individuals. In what is believed to be the first study of its kind,  researchers from the Boston University School of Medicine (BUSM)  have discovered that a specialized eye scanner that accurately measures spectroscopic signals from proteins in lens of the eye can detect and track biological aging in living humans.

According to the researchers, chronological age does not adequately measure individual variation in the rate of biological aging.

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The absence of clinical tools and metrics to quantitatively evaluate how each person is aging at the molecular level represents a major impediment to understanding aging and maximizing health throughout life,” explains corresponding author Lee E. Goldstein, MD, PhD, associate professor of neurology at BUSM.

The lens contains proteins that accumulate aging-related changes throughout life. These lens proteins provide a permanent record of each person’s life history of aging. Our eye scanner can decode this record of how a person is aging at the molecular level.”

The researchers believe these results pave the way for a potentially transformative clinical tool for objective assessment and tracking of molecular aging in humans. “The framework for clinical implementation of this technology to measure molecular aging is similar to other recently adopted clinical biomarkers, including PET brain imaging for Alzheimer’s disease, bone densitometry for osteoporosis and serum blood tests for diabetes mellitus,” adds Dr. Goldstein, who also holds an appointment at Boston University College of Engineering.

While large test batteries incorporating composite metrics have been developed to track human aging, these are far removed from underlying molecular mechanisms of aging and are ill-suited for personalized longitudinal medical care. “By contrast, eye scanning technology that probes lens protein affords a rapid, noninvasive, objective technique for direct measurement of molecular aging that can be easily, quickly, and safely implemented at the point of care. Such a metric affords potential for precision medical care across the lifespan.”

The research team included investigators at Boston University College of Engineering and School of Public Health, Boston Children’s Hospital, Massachusetts General Hospital, Harvard Medical School and the University of Washington, Seattle.

The findings appear online in Journal of Gerontology: Biological Sciences.

Source: https://www.bumc.bu.edu/

How To Reverse Cellular Aging Process

Central to a lot of scientific research into aging are tiny caps on the ends of our chromosomes called telomeres. These protective sequences of DNA grow a little shorter each time a cell divides, but by intervening in this process, researchers hope to one day regulate the process of aging and the ill health effects it can bring. A Harvard team is now offering an exciting pathway forward, discovering a set of small molecules capable of restoring telomere length in mice. Telomeres can be thought of like the plastic tips on the end of our shoelaces, preventing the fraying of the DNA code of the genome and playing an important part in a healthy aging process. But each time a cell divides, they grow a little shorter. This sequence repeats over and over until the cell can no longer divide and dies.

This process is linked to aging and disease, including a rare genetic disease called dyskeratosis congenita (DC). This is caused by the premature aging of cells and is where the team focused its attention, hoping to offer alternatives to the current treatment that involves high-risk bone marrow transplants and which offers limited benefits.

One of the ways dyskeratosis congenita comes about is through genetic mutations that disrupt an enzyme called telomerase, which is key to maintaining the structural integrity of the telomere caps. For this reason, researchers have been working to target telomerase for decades, in hopes of finding ways to slow or even reverse the effects of aging and diseases like dyskeratosis congenita.

Once human telomerase was identified, there were lots of biotech startups, lots of investment,” says Boston Children’s Hospital’s Suneet Agarwal, senior investigator on the new study. “But it didn’t pan out. There are no drugs on the market, and companies have come and gone.

Source: https://news.harvard.edu/
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https://newatlas.com/

CRISPR Halts Growth of Breast Cancer

Triple-negative breast cancer (TNBC), lacking estrogen, progesterone and HER2 receptors, has the highest mortality rate of all breast cancers. It more frequently strikes women under age 50, African American women, and women carrying a BRCA1 gene mutation. The highly aggressive, frequently metastatic cancer is in urgent need of more effective targeted therapeutics.

A new tumor-targeted CRISPR gene editing system, encapsulated in a nanogel and injected into the body, could offer a genetic treatment, suggest researchers at Boston Children’s Hospital. In a proof-of-principle study, conducted in human tumor cells and live, tumor-bearing mice, the CRISPR system effectively halted the growth of TNBC while sparing normal cells. Peng Guo, PhD,Marsha Moses, PhD and their colleagues have reported the findings in the journal PNAS.

To date, a lack of effective delivery systems has limited the translation of CRISPR gene editing into therapies. One method uses a virus to deliver CRISPR, but the virus cannot carry large payloads and potentially can cause side effects if it “infectscells other than those targeted. Another method packages the CRISPR tools inside a cationic polymer or lipid nanoparticles. But these elements can be toxic to cells, and the body often traps or breaks down the nanoparticles before they reach their destination.

The new approach encapsulates the CRISPR editing system inside a soft “nanolipogel” made up of a nontoxic double layer of fatty molecules and a hydrogel. Antibodies attached to the gel’s surface then guide the CRISPR nanoparticles to the tumor site. (The antibodies are designed to recognize and target ICAM-1, a therapeutic target for TNBC discovered by the Moses Lab in 2014.)

Because the particles are soft and flexible, they can enter cells more efficiently than their stiffer counterparts. Stiffer nanoparticles tend to get trapped by the cell’s ingestion machinery, while the soft particles fused with the tumor cell membrane and delivered their CRISPR payloads directly inside the cell, the researchers found.

Using a soft particle allows us to penetrate the tumor better, without side effects, and with bigger cargo,” says Guo, the study’s first author. “Our system can substantially increase tumor delivery of CRISPR.”

Source: http://discoveries.childrenshospital.org