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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When disease or old age ravage the body, it would be great to turn back the clock by swapping out the damaged cells, replacing them with new ones, like for like. Pluripotent stem cells (PSCs) self-replicate and have the potential in the human body to develop into almost any cell type. As such, they have long held potential in the development of regenerative medicines. But obtaining a steady supply of PSCs proved challenging for a number of reasons.

In 2006, researchers introduced a method to reprogram adult cells into a pluripotent state. These induced pluripotent stem cells (iPSCs) could then be coaxed to differentiate into different cell types. Fifteen years on, iPSC technology has become the basis for many drug development efforts, and it could one day change the outlook for millions of people.

iPSC-based therapies could replace, for example, the neurons that die off in Parkinson’s disease or the retinal tissue damaged by macular degeneration. Or perhaps they could obviate the need for a heart transplant. The technology is a marked change for big pharma.

Neurons, derived from stem cells, have potential to replace those lost to Parkinson’s disease. But delivering the cells, and ensuring they survive and integrate, are still big challenges

“This is a completely different way of looking at medicine—replacing diseased cells rather than drugging them. And we’re right on that precipice,” says Seth Ettenberg, Chief Executive Officer of BlueRock Therapeutics, a biotechnology company headquartered in Cambridge, MA, and a Bayer subsidiary. “It’s an incredibly exciting time for the field.”

Using tools such as gene-editing, researchers are seeking to make iPSC-based treatments more effective. The past few years have seen significant progress in the development of treatments.

Parkinson’s disease (PD) is a neurodegenerative disorder that affects more than ten million people worldwide, characterized by the progressive loss of dopamine-producing midbrain neurons, which causes tremors and other motor and neurological symptoms. Mainstay treatments can alleviate symptoms, but do not halt disease progression.

Researchers hope that iPSC-based therapies could replace the neurons killed as Parkinson’s disease progresses. Dopamine-producing neurons derived from iPSCs have been shown to improve behaviour in a rat model of PD. In one patient, dopamine cells from autologous iPSCs seemed to stabilize or even slightly improve motor symptoms 18-24 months after transplantation.

The brain is a difficult organ to access, however. “Cells will be administered to the midbrain via neurosurgery using devices designed to ensure cells are not damaged during delivery,” says Stefan Frank, associate director of Bayer’s iPSC platform strategy. “The cells then need to stay there, survive and integrate.”

Source: https://www.nature.com/

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/

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/

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/