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Discovery
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Regina Kelder

The New Era of CNS Discovery

Are we moving the needle in CNS diseases? Highlights from Neuroscience Day

Despite enormous efforts to come up with new options that advance our ability to treat CNS diseases, researchers have had limited success. In instances where we have managed to get novel treatments to patients, the drugs are often reformulated versions of existing medications. This lack of success has been due to the high failure rate of CNS drugs in Phase II & III trials, even when the clinical candidates demonstrated a clear efficacy signal in animal models.

So where can we go to find solutions? Yesterday’s Neuroscience Day 2020: Enter the New Era of CNS Discovery, a virtual event sponsored by Charles River, provided some cutting edge ideas on how we might be able to move the needle in a positive direction for some of the toughest neurodegenerative diseases. 

Novel imaging approaches in Alzheimer’s

White matter, the tissue through which messages pass between different areas of grey matter within the CNS, is altered in people with Alzheimer’s. A high percentage of Alzheimer’s patients show signs of white matter degeneration, such as the death of oligodendrocytes, cells that help neurons function.
It is not surprising, therefore, that being able to image white matter axons and identify the biomarkers driving these white matter changes is a kind of “holy grail” in neuroscience. Being able to detect these changes at the micro level might provide some clues on what is causing the degeneration and how to prevent it.

Neuroscientist Maxime Descoteaux PhD, a professor at the Université of Sherbrooke in Canada discussed how his lab is combining the use of diffusion MRI (dMRI)—a tool that can be used to study the architecture of white matter—with free water modeling to measure inflammation-associated edema in the brains of individuals with Alzheimer’s. The integrated approach enables researchers to reconstruct cross-fiber activity in white matter not detectable using just MRI. 

Descoteaux likens this to being able to take a satellite image of a freeway and then zeroing in on all of the cars to track their movements with exquisite detail. Except Descoteaux’s team is tracking the free water circulating in the white matter compartments, and using it as a biomarker to measure inflammation in the brains of healthy individuals, those with mild cognitive impairment and those with full-blown Alzheimer’s. 
Not only does this integrate approach open a window into which sections of white matter might be influencing neurodegeneration, it’s also a way of measuring the impact of CNS drugs on Alzheimer’s. Descoteaux says an early stage clinical trial using free water analysis has been able to show an that anti-inflammatory drug is working in the brain, suggesting the tool might be useful for future drug studies.

 Cell and gene therapies

Some of the most exciting developments in CNS research are occurring on the cell and gene therapy fronts.  Howard Federoff, MD, PHD, the chief executive officer of Aspen Biosciences, described work his lab is doing to develop a gene therapy for Parkinson’s disease using autologous transplantation, which uses cells derived from the patient rather than an unrelated donor. 
Though most cases of PD are sporadic, Federoff’s company is concentrating on a small subset of PD patients whose disease is inherited. Specifically, they are looking at a common mutation found in the gene GBA. The stem cell product being developed at Aspen Biosciences replaces lost dopamine neurons—which is widely thought to be one of the causes of Parkinson’s—and transplants cells that produce normal levels of dopamine.

While many labs are using induced pluripotent stem cells to develop their therapies, Aspen Biosciences is unusual in that it uses a patient’s own stem cells to develop its neuron therapy. Federoff says this approach is beneficial for two reasons. First, because the transplanted cells come from the same person there is no risk of graft-versus-host disease and therefore no need for immunosuppressive drugs. Additionally, it a second transplant is needed years later it can be done  without threat of rejection as cells will be coming from the same individual. 

Aspen Biosciences currently is developing two stem cell products, one for a sporadic form of PD, and another for an inherited form. 

Scientists are also using iPSCs in the pursuit of AD therapies. Shushant Jain, PhD, a Research Leader at Charles River’s Early Discovery site in Leiden described work his lab is doing to differentiate the stem cells into neurons in order to recapitulate the phenotypes relevant to AD. To do this they have been partnering with the company BitBio, whose scalable platform produces consistent batches of stem cells in a matter of weeks

Jain’s lab has been able to transfer a protein that controls the creation of neurons into iPSCs, and then get the stem cells to express the protein in an inducible manner.  They are also experimenting with the gene editing tool, CRISPR-Cas9.