MJFF Grant Will Help Inflazome Develop Brain-imaging Probe for Parkinson’s Research

Inflazome, funding

The Michael J. Fox Foundation for Parkinson’s Research (MJFF) has granted more than $1 million to Inflazome to fund the development of a brain-imaging probe that may help track progression of Parkinson’s and develop new therapies for the disease.

The funding will help develop a positron emission tomography (PET) tracer specific to a cellular sensor of stress known as the NLRP3 inflammasome, and may enable quick, accurate and non-invasive imaging of brain inflammation, according to Inflazome.

Such a tool could increase the likelihood of success in clinical trials by  helping to select suitable patients at the appropriate disease stage, and providing a way to determine whether a treatment candidate binds to the target of interest in the brain, the company believes. The tracer also will help Inflazome determine what doses are needed in clinical trials.

The NLRP3 inflammasome is a multiprotein complex believed to drive chronic inflammation in Parkinson’s and other neurodegenerative diseases. A recent study in postmortem brains from Parkinson’s patients and mouse models of the disease showed that this inflammasome is activated by aggregated alpha-synuclein, the main component of Lewy bodies, and loss of dopamine-producing nerve cells. Both Lewy bodies and death of dopaminergic neurons are hallmarks of Parkinson’s.

Then, the researchers found that MCC950, an oral small-molecule blocker of the NLRP3 inflammasome, completely suppressed inflammasome activation in microglia, a key cell type in immune responses in the central nervous system (brain and spinal cord). MCC950 also inhibited alpha-synuclein clumping, prevented the loss of nerve cells, and eased motor deficits in a mouse model of Parkinson’s disease.

In a press release, Matthew Cooper, Inflazome’s co-founder and CEO, said The Michael J. Fox Foundation is a fantastic organization with a passionate commitment to new science, science translation and candidate therapies for Parkinson’s.”

Cooper, a co-author of the preclinical study and the principal investigator in the newly funded project, also mentioned that Inflazome and MJFF “are fully aligned” to help people with Parkinson’s and other neurodegenerative diseases with unmet medical needs. “Their support will help us advance and hopefully validate our disruptive approach to diagnose and then treat patients by focusing on neuroinflammation.”

Jamie Eberling, director of research programs at MJFF, said that having a tool to visualize brain inflammation “may help investigate Parkinson’s onset and progression as well as evaluate new treatments that could alter the course of the disease.” Eberling also said that MJFF “is investing in this research due to the significant potential impact on drug development and patient lives.”

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Repurposed Therapies, New Compounds to Be Tested to Block Brain Inflammation in Parkinson’s

brain inflammation

Researchers in Australia are planning to test therapies already being used in other inflammatory conditions, as well as new compounds, for their potential to block brain inflammation and halt Parkinson’s disease progression.

Conducted by researchers at The University of Queensland (UQ) in Australia, the study, “Pharmacological Targeting of Inflammasome Activation Mechanisms in Synuclein Models of Parkinson’s Disease,” is made possible by a two-year research grant funded by The Michael J. Fox Foundation for Parkinson’s Research and Shake It Up Australia Foundation.

Queensland researchers had previously found evidence supporting the activation of an immune system complex called the inflammasome in chronic inflammation and loss of brain cells in Parkinson’s. They also found a new signaling pathway through which toxic forms of the protein alpha-synuclein — the main component of the Parkinson’s hallmark Lewy bodies — activate the inflammasome.

The scientists also showed that this pathway is activated in isolated immune cells from Parkinson’s patients and in preclinical models of the disease. These preclinical experiments also revealed that blocking the pathway with a repurposed therapy — which refers to treatments already approved by regulatory agencies for other indications — was beneficial.

“In our previous study, we were trying to ‘cool brains on fire’ from inflammation whereas this time we’re focusing on stopping that fire from starting in the first place,” Richard Gordon, PhD, a group leader at the UQ Centre for Clinical Research who will be leading the research, said in a press release.

The team will now assess a new therapeutic strategy to slow or halt Parkinson’s progression by blocking chronic activation of the immune system and brain inflammation.

They will be testing a set of more effective and targeted compounds, both new and repurposed, intended to block the activation of the inflammasome in preclinical models. If effective, the study will provide the basis for clinical trials in patients, according to the researchers.

“If we can prove they work in treating Parkinson’s disease, we can repurpose these and get them to the clinic to treat patients faster than developing new drugs,” Gordon said.

“Brain inflammation is a key area of Parkinson’s research,” said Clyde Campbell, Shake It Up Australia’s founder and CEO, adding that new treatments “can rapidly progress to clinical trials” through the Queensland Drug Repurposing Initiative, a UQ partnership with the Cure Parkinson’s Trust and the international Linked Clinical Trials Initiative, funded by the Advance Queensland program and Shake It Up Australia.

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MJ Fox Foundation Gives Therapeutic Pipeline Award to Progenra, Supporting Work on New Therapies

Progenra, award, Michael J. Fox Foundation

The Michael J. Fox Foundation for Parkinson’s Research (MJFF) has granted a 2018 Therapeutic Pipeline Award to Progenra to support the company’s development of small molecule treatment candidates for Parkinson’s disease.

“Progenra is pleased to have been selected by The Michael J. Fox Foundation to contribute to bringing Parkinson’s and other major neurodegenerative diseases under control by introducing new therapeutic agents,” Tauseef Butt, Progenra’s president and CEO, said in a press release.

The company’s goal is to find new medicines that target enzymes in the ubiquitin proteasome system (UPS). The UPS has been implicated in neurodegenerative diseases, based on the observation of protein deposits tagged with ubiquitin — a marker for degradation in cellular structures called proteasomes — in affected neurons.

Research has shown that impaired UPS function, due to the accumulation of aggregation-prone proteins, delays the degradation of substrates important in cellular processes such as signaling and apoptosis — which refers to “programmed” cell death, rather than death caused by injury — ultimately leading to neurodegeneration.

“We believe that augmenting the activity of a native enzyme known to be beneficial in combating neurodegeneration will provide both mechanistic information and the potential for breakthrough treatment,” Butt stated. “We look forward to working with the many excellent researchers in the foundation’s consortium.”

MJFF’s Therapeutic Pipeline Program grants awards to projects of clinical utility for patients and to proposals believed to have the potential to alter disease course and/or significantly improve treatment over the current standards of care.

Both industry and academic investigators may apply by proposing new strategies or clinically safe therapies used in other diseases. The program covers development from preclinical studies to clinical trials, which includes pharmacological and non-pharmacological approaches such as gene therapy, biological, surgical, and non-invasive methods.

In addition, MJFF’s Target Advancement Program aims to overcome the need for well-validated targets in the disease process. It seeks to foster critical target validation studies that may ultimately speed up subsequent therapy development. The program also supports continuing work on established targets — those already showing links to the disease in patients.

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Researchers Receive Funding to Study New Gene Linked to Parkinson’s Disease

gene linked to Parkinson's

A multidisciplinary research team at Purdue University in Indiana and the University of Bordeaux in France was awarded a $107,000 grant by the The Michael J. Fox Foundation for Parkinson’s Research to study the neuroprotective ability of a newly discovered gene associated with Parkinson’s disease.

The gene was discovered by Jean-Christophe Rochet, PhD, a professor of medicinal chemistry and molecular pharmacology at Purdue, when he and Min Zhang, PhD, a professor of statistics at Purdue, identified a list of genes related to Parkinson’s by analyzing several data sets obtained from one of the National Institutes of Health-Designated Data Repositories.

“While some of the genes on the list were already known, Chris [Rochet] found an interesting gene that has not been reported to be directly associated with Parkinson’s disease yet,” Zhang said in a press release.

The gene, called NFE2L1, produces a protein that controls other genes involved in the survival and maturation of dopaminergic neurons.

Parkinson’s disease is caused by the impairment or death of these dopamine-producing nerve cells, or neurons, in a region of the brain called the substantia nigra, which controls the body’s balance and movement.

“NFE2L1 levels are reduced in dopaminergic neurons in the brains of Parkinson’s disease patients,” Rochet said. “We recently found in a large-scale genomic study that a minor allele of NFE2L1 can lower Parkinson’s risk. These observations imply that neuron death in Parkinson’s disease may result in part from a loss of the neuroprotective action of NFE2L1.”

Researchers hypothesize that increasing the production of the NFE2L1 protein in rodent models of Parkinson’s disease will reduce nerve cell death.

The team then intends to screen for compounds that can increase NF2L1 levels in the brain, either by stimulating its production or by blocking its degradation by the proteasome, a protein complex that destroys unnecessary or damaged proteins.

This research will not only shed light on the protein’s ability to reduce neurotoxicity, but the team also hopes it will aid in the development of Parkinson’s therapies that target NFE2L1 levels in the brain.

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Alkahest Awarded Grant to Support Development of ALK4290 for Parkinson’s


The Michael J. Fox Foundation for Parkinson’s Research (MJFF) recently awarded Alkahest a grant to support the development of ALK4290 as a new therapy for Parkinson’s disease.

The immune system plays an important role in the development and progression of Parkinson’s disease. New therapies targeting the recruitment of immune cells, or inhibiting brain inflammation, could be effective in treating the disease.

ALK4290 is an oral, small molecule medicine that acts as a key modulator of inflammation, with potential effects on multiple symptoms associated with Parkinson’s disease.

The investigational compound has been well-tolerated in previous clinical studies and is currently being studied in wet age-related macular degeneration (wAMD), a medical condition that frequently leads to vision loss in the center of the visual field.

Both studies (ALK4290-201 and ALK4290-202) are open-label Phase 2 clinical trials evaluating the therapeutic effects and safety of a six-week oral treatment regimen of ALK4290 in patients with either newly diagnosed wAMD or refractory wAMD. Both studies will be conducted in Europe (Hungary and Poland).

The MJFF grant will test whether ALK4290 can be used to treat Parkinson’s disease. Researchers will evaluate the effect of ALK4290 in two pre-clinical models relevant to Parkinson’s disease biology and will assess whether ALK4290 reverses deficits in motor function and loss of neurons through inhibition of inflammation in these animal models.

This project will attempt to determine the mechanisms underlying immune cell involvement in Parkinson’s disease, providing further support for the link between neuroinflammation and disease progression. If the study proves successful, the compound will rapidly enter clinical testing to evaluate its potential benefits for Parkinson’s patients.

“Parkinson’s disease is a condition with significant impact on patients whose needs are still unmet. We are excited about the prospects of evaluating ALK4290 as a novel therapeutic in this indication and continuing our commitment to developing innovative treatments for age-related disorders,” Steven Braithwaite, Alkahest’s chief scientific officer, said in a press release.

“Our Foundation funds novel approaches to slow or stop Parkinson’s progression, the greatest unmet need for the millions living with this disease,” added Liliana Menalled, PhD, MJFF senior associate director of research programs. “The ALK4290 molecule shows strong data to support additional evaluation as a potential Parkinson’s therapy, and we look forward to seeing the results of Alkahest’s experiments.”

The grant, “Development of ALK4290 as a novel PD therapeutic,” will be coordinated by S. Sakura Minami, PhD, who has 15 years of research experience in the field of neuroscience. She leads her research group at Alkahest, Inc., a biotech company located in the San Francisco Bay area, to better understand the mechanisms underlying aging and to develop therapies for age-related diseases.

ALK4290 was acquired by Alkahest from Boehringer Ingelheim with exclusive rights for its development and commercialization worldwide.

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Source: Parkinson's News Today

Charles River Laboratories, Michael J. Fox Foundation Extend Research Partnership

Charles River Laboratories

Charles River Laboratories International and The Michael J. Fox Foundation for Parkinson’s Research (MJFF) extended their collaboration to accelerate the discovery of Parkinson’s disease therapies.

The extension covers grants from MJFF to characterize two animal models of Parkinson’s — one where mice do not express alpha-synuclein (knockout), and another where mice express the Parkinson’s-associated alpha-synuclein mutant A53T (knockin). Alpha-synuclein is the major component of Lewy bodies, the characteristic protein clumps of Parkinson’s disease.

Charles River and MJFF also renewed their partnership to continue to develop and test new small molecules that inhibit the LRRK2 kinase, whose mutations are associated with the development of sporadic and familial cases of Parkinson’s.

Two LRRK2 inhibitors, currently being evaluated to treat Parkinson’s in two Phase 1 clinical trials, already have shown promising initial results.

Researchers want to establish optimal dosing strategies for efficient LRRK2 inhibitors, while avoiding lung changes that have been reported in previous preclinical studies in animal models.

Charles River will work on these projects for the next two years,  providing novel preclinical tools for drug development in Parkinson’s disease.

“We are enthusiastic about the start of our new project,” Robert Hodgson, PhD, director In Vivo CNS, Integrated Drug Discovery at Charles River, said in a press release. “It is extremely rewarding for our teams to know that they are making visible progress toward bringing a novel [Parkinson’s] therapy to the clinic.”

Nicole Polinski, PhD, associate director of Research Programs at MJFF, added: “The Michael J. Fox Foundation is committed to advancing tools and pre-clinical models that speed Parkinson’s research toward urgently needed breakthroughs for patients.”

Polinski also underscored Charles River’s portfolio of early discovery services. “We look forward to seeing the outcomes of these projects, which may have a significant impact on development of new treatments for the millions living with this disease,” she said.

MJFF is the largest private funder of Parkinson’s research worldwide and collaborates with pharmaceutical companies, academic scientists and government research funders. The foundation also is involved in improving patient recruitment for clinical trials with its online tool, Fox Trial Finder, and in promoting disease awareness.

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Michael J. Fox Foundation Announces New $7M Initiative to Support Parkinson’s Research, Therapy Development

Michael J. Fox Foundation

The Michael J. Fox Foundation (MJFF) announced a new $7 million funding program to support Parkinson’s disease research and accelerate development of new therapeutic targets and biomarkers.

Through the program, researchers can request project funding in four major research areas. The organization is now accepting pre-proposals through May 2018, with funding anticipated by November 2018.

“We are working diligently toward breakthroughs for people with Parkinson’s and are committed to helping make therapy options available to treat the disease,” Todd Sherer, PhD, chief executive officer of MJFF, said in a press release. “The targeted funding programs announced today will fuel cutting-edge research in areas of significant scientific potential, providing multiple shots on goal.”

One of the four research areas will dedicate $2 million to study nonpharmacological interventions for gait and balance disturbances, two of the most troubling and under-addressed aspects of the disease.

Parkinson’s patients suffer from frequent falls, injury, loss of independence, and decreased quality of life due to problems with gait and balance. Current therapies are insufficient to improve challenges in this area.

The program will fund research projects seeking to gain a deeper insight of the brain circuitry and clinical experience of gait and balance problems. It will also fund studies to investigate the therapeutic benefit of assistive devices, novel technologies, or rehabilitative therapy programs. Excluded from this funding are exercise programs or cognitive strategies.

An additional $1.5 million will be geared toward studying the protein alpha-synuclein, the major component of Lewy bodies, protein clumps found in virtually every Parkinson’s patient’s brain and body cells. To test if Lewy bodies may play a causal role in the disease’s onset and progression, the program will fund researchers seeking to deepen understanding of alpha-synuclein and refine therapy development.

The foundation has also allocated $1.5 million to fund projects investigating GBA protein dysfunction and mutations in the GBA gene in Parkinson’s and speed learning toward practical therapies.

GBA mutations are among the most common in Parkinson’s disease, found in 5 to 10 percent of patients. However, alterations of the normal GBA protein have been found in patients who are not carriers of the GBA mutation, making it a particularly promising target in the development of new therapeutic targets.

A fourth area of research will have a dedicated budget of $2 million. The program will fund researchers seeking to develop and test biomarker assays in three relevant areas: protein handing/autophagy, exosomes, and lipidomics.

Objective measures of Parkinson’s risk, onset, and progression are critical to transform patient care and therapy development. Biomarkers are not only useful to enable an early and accurate diagnosis, but they are also particularly important for more efficient, cost-effective clinical trials. To date, no objective biomarker for Parkinson’s has been developed.

The deadline for pre-proposal submissions is 5:00 p.m. EST May 31, 2018.

MJFF will host an informational webinar at 12:00 p.m. EST May 10 to review the aims of the program and to detail funding process and applicant questions.

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Source: Parkinson's News Today