In almost 70 years, our understanding of how Parkinson’s disease wreaks havoc on the nervous system has grown tremendously. Advances in genetic sequencing, for instance, have revealed that up to 15 percent of all cases of Parkinson’s can be attributed to inherited mutations in a person’s DNA. But large gaps in our understanding remain, including what causes the majority of cases and how to definitively test for the disease. Most astonishingly, today’s gold standard treatment for Parkinson’s—levodopa medications—was discovered 68 years ago. Levodopa is effective at reducing Parkinson’s hallmark symptoms like tremors, slowness, and stiffness. The underlying theory is that Parkinson’s patients lose cells that make dopamine, and levodopa acts as a substitute.

Crucially, however, levodopa cannot stop or slow the progression of the neurodegenerative disease—merely provide some respite to the symptoms. Many researchers hope to find a more permanent cure by targeting the source and directly fixing mistakes in patients’ genes that lead to Parkinson’s in the first place. In a new study published April 19 in the journal Science Advances, one group reports having acquired the ability to overcome a (literal) barrier holding genetic intervention back.

New ways to treat Parkinson’s disease can’t come fast enough. More than 8.5 million people worldwide have the disease, and it’s the fastest-growing neurological cause of disability and death. Not only can these new findings introduce a new generation of Parkinson’s treatments, it could fundamentally change the way we treat diseases of the brain.

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Researchers from Sanford Burnham Prebys have discovered a group of proteins that could be key for cellular reprogramming, a growing topic in regenerative medicine. So far, scientists have been using the technology to repair damaged or injured body tissues. In this study, the scientists successfully reprogrammed damaged heart cells to repair heart injuries in mice after a heart attack. The findings could be pivotal for treating not just heart diseases, but Parkinson’s and neuromuscular diseases as well.

“Even if a person survives a heart attack, there could still be long-term damage to the heart that increases the risk of heart problems down the line,” says lead author Alexandre Colas, Ph.D., an assistant professor in the Development, Aging and Regeneration Program at Sanford Burnham Prebys, in a media release. “Helping the heart heal after injury is an important medical need in its own right, but these findings also pave the way for wider applications of cell reprogramming in medicine.”

The four proteins identified are called AJSZ, and they help address the barriers to reprogramming. The team was able to block the proteins, lessening scarring, and leading to an improvement in overall heart function by 50 percent. Even though these findings are relative to heart cells, the researchers say that the proteins are universal to all cell types. “This is helping us solve a very big problem that a lot of researchers are interested in,” says Colas. “Even more important, this breakthrough is a significant step forward on our way to turning these promising biological concepts into real treatments.”

In the near future, the team hopes to take this great discovery and start applying it to real-life patients by identifying different ways to block AJSZ function swiftly and effectively. The best option right now is using a small molecule drug to do so, Colas explains. “We need to find a way to inhibit these proteins in a way we can control to make sure we are only reprogramming the cells that need it,” the researcher concludes. “We will be screening for drugs that can help us inhibit these proteins in a controlled and selective manner in the coming months.”

Source: https://www.sbpdiscovery.org/

Voices offer lots of information. Turns out, they can even help diagnose an illness — and researchers are working on an app for that. The National Institutes of Health is funding a massive research project to collect voice data and develop an AI that could diagnose people based on their speech. Everything from your vocal cord vibrations to breathing patterns when you speak offers potential information about your health, says laryngologist Dr. Yael Bensoussan, the director of the University of South Florida’s Health Voice Center and a leader on the study.

“We asked experts: Well, if you close your eyes when a patient comes in, just by listening to their voice, can you have an idea of the diagnosis they have?” Bensoussan says. “And that’s where we got all our information.”

Someone who speaks low and slowly might have Parkinson’s disease. Slurring is a sign of a stroke. Scientists could even diagnose depression or cancer. The team will start by collecting the voices of people with conditions in five areas: neurological disorders, voice disorders, mood disorders, respiratory disorders and pediatric disorders like autism and speech delays. The project is part of the NIH‘s Bridge to AI program, which launched over a year ago with more than $100 million in funding from the federal government, with the goal of creating large-scale health care databases for precision medicine.

“We were really lacking large what we call open source databases,” Bensoussan says. “Every institution kind of has their own database of data. But to create these networks and these infrastructures was really important to then allow researchers from other generations to use this data.” This isn’t the first time researchers have used AI to study human voices, but it’s the first time data will be collected on this level — the project is a collaboration between USF, Cornell and 10 other institutions. “We saw that everybody was kind of doing very similar work but always at a smaller level,” Bensoussan says. “We needed to do something as a team and build a network.”

The ultimate goal is an app that could help bridge access to rural or underserved communities, by helping general practitioners refer patients to specialists. Long term, iPhones or Alexa could detect changes in your voice, such as a cough, and advise you to seek medical attention.

Source: https://www.npr.org/

A research team at Washington University School of Medicine in St. Louis has identified potential new treatment targets for Alzheimer’s disease, as well as existing drugs that have therapeutic potential against these targets.

The potential targets are defective proteins that lead to the buildup of amyloid in the brain, contributing to the onset of problems with memory and thinking that are the hallmark of Alzheimer’s. The 15 existing drugs identified by the researchers have been approved by the Food and Drug Administration (FDA) for other purposes, providing the possibility of clinical trials that could begin sooner than is typical, according to the researchers.

In addition, the experiments yielded seven drugs that may be useful for treating faulty proteins linked to Parkinson’s disease, six for stroke and one for amyotrophic lateral sclerosis (ALS).

Scientists have worked for decades to develop treatments for Alzheimer’s by targeting genes rooted in the disease process but have had little success. That approach has led to several dead ends because many of those genes don’t fundamentally alter proteins at work in the brain. The new study takes a different approach, by focusing on proteins in the brain, and other tissues, whose function has been altered.

“In this study, we used human samples and the latest technologies to better understand the biology of Alzheimer’s disease,” said principal investigator Carlos Cruchaga, the Reuben Morriss III Professor of Neurology and a professor of psychiatry. “Using Alzheimer’s disease samples, we’ve been able to identify new genes, druggable targets and FDA-approved compounds that interact with those targets to potentially slow or reverse the progress of Alzheimer’s.”

The scientists focused on protein levels in the brain, cerebrospinal fluid (CSF) and blood plasma of people with and without Alzheimer’s disease. Some of the proteins were made by genes previously linked to Alzheimer’s risk, while others were made by genes not previously connected to the disease. After identifying the proteins, the researchers compared their results to several databases of existing drugs that affect those proteins.

The new study, funded by the National Institute on Aging of the National Institutes of Health (NIH), is published in the journal Nature Neuroscience.

Source: https://source.wustl.edu/

Children with a devastating genetic disorder characterized by severe motor disability and developmental delay have experienced sometimes dramatic improvements in a gene therapy trial launched at UC San Francisco Benioff Children’s Hospitals. The trial includes seven children aged 4 to 9 born with deficiency of AADC, an enzyme involved in the synthesis of neurotransmitters, particularly dopamine, that leaves them unable to speak, feed themselves or hold up their head. Six of the children were treated at UCSF and one at Ohio State Wexner Medical Center.

Children in the study experienced improved motor function, better mood, and longer sleep, and were able to interact more fully with their parents and siblings. Oculogyric crisis, a hallmark of the disorder involving involuntary upward fixed gaze that may last for hours and may be accompanied by seizure-like episodes, ceased in all but one patient. Just 135 children worldwide are known to be missing the AADC enzyme, with the condition affecting more people of Asian descent.

The trial borrowed from gene delivery techniques used to treat Parkinson’s disease, pioneered by senior author Krystof Bankiewicz, MD, PhD, of the UCSF Department of Neurological Surgery and the Weill Institute for Neurosciences, and of the Department of Neurological Surgery at Ohio State University. Both conditions are associated with deficiencies of AADC, which converts levodopa into dopamine, a neurotransmitter involved in movement, mood, learning and concentration. In treating both conditions, Bankiewicz developed a viral vector containing the AADC gene. The vector is infused into the brain via a small hole in the skull, using real-time MR imaging to enable the neurosurgeon to map the target region and plan canula insertion and infusion.

“Children with primary AADC deficiency lack a functional copy of the gene, but we had presumed that their actual neuronal pathway was intact,” said co-first author Nalin Gupta, MD, PhD, of the UCSF Department of Neurological Surgery and the surgical principal investigator. “This is unlike Parkinson’s disease, where the neurons that produce dopamine undergo degeneration.”

While the Parkinson’s trial focused on the putamen, a part of the brain that plays a key role in this degeneration, Gupta said the AADC gene therapy trial targeted neurons in the substantia nigra and ventral tegmental area of the brainstem, sites that may have more therapeutic benefits.

“The approach for treating AADC deficiency is much more straightforward than it is for Parkinson’s,” said Bankiewicz. “In AADC deficiency, the wiring of the brain is normal, it’s just the neurons don’t know how to produce dopamine because they lack AADC.”

Results appear in Nature Communications.

Source: https://www.ucsf.edu/

Tesla CEO Elon Musk released a video showing how his company Neuralink – a brain-computer-interface company – had advanced its technology to the point that the chip could allow a monkey to play video games with its mind.

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Neuralink could transition from operating on monkeys to human trials within the year, if the startup meets a previous prediction from Musk. In February, he said the company planned to launch human trials by the end of the year after first mentioning his work with the monkey implants.

At the time, the CEO gave the timeline in response to another user’s request to join human trials for the product, which is designed to implant artificial intelligence into human brains as well as potentially cure neurological diseases like Alzheimer’s and Parkinson’s.

Musk has made similar statements in the past about his project, which was launched in 2016. He said in 2019 that it would be testing on humans by the end of 2020.

There has been a recent flurry of information on the project. Prior to the recent video release on Twitter, Musk had made an appearance on the social media site, Clubhouse, and provided some additional updates on Neuralink back in February.

During his Clubhouse visit, Musk detailed how the company had implanted the chip in the monkey’s brain and talked about how it could play video games using only its mind.

Source: https://www.sciencealert.com/

Grafting neurons grown from monkeys’ own cells into their brains relieved the debilitating movement and depression symptoms associated with Parkinson’s disease, researchers at the University of Wisconsin–Madison (UW) reported today.

In a study published in the journal Nature Medicine, the UW team describes its success with neurons made from induced pluripotent stem cells from the monkeys’ own bodies. This approach avoided complications with the primates’ immune systems and takes an important step toward a treatment for millions of human Parkinson’s patients.

“This result in primates is extremely powerful, particularly for translating our discoveries to the clinic,” says UW–Madison neuroscientist Su-Chun Zhang, whose lab grew the brain cells.

Parkinson’s disease damages neurons in the brain that produce dopamine, a brain chemical that transmits signals between nerve cells. The disrupted signals make it progressively harder to coordinate muscles for even simple movements and cause rigidity, slowness and tremors that are the disease’s hallmark symptoms. Patients — especially those in earlier stages of Parkinson’s — are typically treated with drugs like L-DOPA to increase dopamine production.

“Those drugs work well for many patients, but the effect doesn’t last,” says Marina Emborg, a Parkinson’s researcher at UW–Madison’s Wisconsin National Primate Research Center. “Eventually, as the disease progresses and their motor symptoms get worse, they are back to not having enough dopamine, and side effects of the drugs appear.”

Scientists have tried with some success to treat later-stage Parkinson’s in patients by implanting cells from fetal tissue, but research and outcomes were limited by the availability of useful cells and interference from patients’. Zhang’s lab has spent years learning how to dial donor cells from a patient back into a stem cell state, in which they have the power to grow into nearly any kind of cell in the body, and then redirect that development to create neurons.

“The idea is very simple,” Zhang says. “When you have stem cells, you can generate the right type of target cells in a consistent manner. And when they come from the individual you want to graft them into, the body recognizes and welcomes them as their own.”

Source: https://news.wisc.edu/

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/

While adult stem cells have long been used to treat a handful of blood and immune disorders, the excitement has centered on two more versatile varieties: embryonic stem cells (ESCs) and  induced pluripotent stem cells (iPSCs), both of which can be transformed into any cell type in the body.

The New England Journal of Medicine published the first case report from a study using custom-grown stem cells to treat Parkinson’s disease in humans. The debilitating condition, which affects 10 million people worldwide, primarily results from the loss of neurons that produce the neurotransmitter dopamine. Existing treatments have had limited success. Stem cell researchers aim to replace dying neurons with healthy ones grown in the lab. The neurosurgeon Jeffrey Schweitzer at Massachusetts General Hospital and neurobiologist Kwang-Soo Kim at McLean Hospital — used what are known as autologous iPSCs. These are stem cells generated from the recipient’s own mature cells, which greatly reduces the likelihood that immunosuppressants will be needed to prevent rejection. The team collected skin cells from a 69-year-old man and reprogrammed them into iPSCs. They then guided the stem cells to take on the characteristics of dopaminergic neurons, which they implanted into the patient’s putamen, a brain region implicated in Parkinson’s. Over a 24-month period, PET scans showed evidence that the new cells were functional. The man’s motor symptoms and quality-of-life scores improved, while his daily medication requirement decreased. He experienced no side effects or complications.

Dopaminergic neurons can be derived from induced pluripotent stem cells, or iPSCs

“This represents a milestone in ‘personalized medicine’ for Parkinson’s,” Kim wrote in a statement. It also represented a milestone for the patient — George “Doc” Lopez, a physician-turned-medical equipment entrepreneur, whose financial contributions to Kim’s research helped make the surgery possible.

Source: https://www.discovermagazine.com/

Transferring lab grown neurons into animal brains reduces the cells’ viability — their chances of integrating well into the tissue — and the efficiency with which they can restore function. So scientists at Shanghai Research Center for Brain Science and Brain–Inspired Intelligence fashioned a method to regenerate neurons inside the brain. The method is similar to how one would revive a dying plant: by nurturing it with the right conditions for it to grow new leaves.

Building up on a previous study, Haibo Zhou, a postdoctoral researcher in Hui Yang’s lab, and colleagues, set up a method to convert non neuronal brain cells called “glia” into neurons. They did this by turning down a gene called PTBP1 in glia of different parts of the mouse brain, using the gene-editing tool CRISPR. Depending on which brain region was targeted, the glia gave rise to different kinds of neurons.

Reducing PTBP1 levels presumably reverted glia to unspecified stem cells, which adopted varied neuronal identities based on which glia were targeted and the environmental signals they received. This was evident from the team’s successful attempts at restoring two different types of neurons and alleviating the symptoms associated with the loss of each.

Parkinson’s disease occurs due to loss of dopamine-producing neurons and manifests as tremors, stiffness, and loss of balance. To test their method in rejuvenating this group of neurons, the team first got rid of them using a toxic compound in mice. The authors then converted glia into dopamine-producing neurons, and the new cells showed the same activity as their original counterparts.

This rescue was not limited to just the neuron population. It also partially restored the normal motor behavior of the animal. This is a huge step forward from drug induced alleviation of symptoms because it puts forth a more permanent solution.

The team also tackled retinal diseases caused by death of retinal ganglion cells, or RGCs, which leads to permanent blindness. Turning down PTBP1 in glia of the retina transformed them into RGCs. Astoundingly, these renewed neurons not only responded to light independently, but also sent their projections to the visual cortex correctly, restoring circuit function. This led to a partial recovery of eyesight in the treated mice.

Source: https://www.salon.com/