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Fox Foundation Awards AC Immune New Grant to Advance Alpha-Synuclein Imaging Agent

Grant award

The Michael J. Fox Foundation for Parkinson’s Research (MJFF) has awarded AC Immune a new grant to further the development of tracer compounds for Parkinson’s disease (PD).

Specifically, this award continues MJFF support for AC Immune’s alpha-synuclein positron-emission tomography (PET) tracer program, aiming for an accurate imaging agent of the alpha-synuclein protein clumps in nerve cells of the brain that are thought to underlie Parkinson’s development and progression.

Positron-emission tomography (PET) is a non-invasive imaging technique that enables the visualization of the metabolic processes in the body. A PET tracer that is alpha-synuclein specific would allow scientists to study the distribution and alterations of these toxic clumps as the disease progresses.

AC Immune researchers has identified several PET tracer compounds with high affinity and selectivity to alpha-synuclein deposits. They did so by screening the company’s library of small molecules for suitable alpha-synuclein PET tracer candidates.

This “molecular collection,” also known as the Morphomer platform, enables the identification of a new class of low molecular weight compounds. This platform, in turn, allows for the generation of small molecules — called morphomers — that specifically bind to misfolded proteins, working to break up the neurotoxic clusters and prevent protein aggregation.

Importantly, these molecules can reach the brains of non-human primates, adding to their potential as a central nervous system tracer.

A lead alpha-synuclein PET tracer candidate, ACI-3024, entered a Phase 1 clinical trial of its ability to capture pathological alpha-synuclein in neurodegenerative diseases like Parkinson’s. The study is assessing the safety, tolerability, and interactions between the body and ACI-3024 (pharmacokinetics and pharmacodynamics) in healthy volunteers.

Jan Stöhr, PhD, head of Non-Alzheimer’s Disease Proteinopathies at AC Immune, will give an oral presentation about this alpha-synuclein PET tracer program at the Fox Foundation’s 13th Annual PD Therapeutics Conference set for Oct. 15 in New York City.

“We are very proud to be working together with MJFF on our a-syn [alpha-synuclein] PET tracer program, which offers patients the potential for earlier diagnosis of PD and facilitates the development … of imaging agents capable of earlier detection and disease monitoring, as well as the development of a broad pipeline of effective therapeutic candidates focused on the prevention and treatment,” Andrea Pfeifer, PhD, CEO of AC Immune, said in a news release.

The Fox Foundation first began supporting AC Immune’s program for alpha-synuclein-specific tracer compounds in 2015. If the program is successful, it could offer a first imaging agent capable of accurately identifying and monitoring Parkinson’s progression.

AC Immune is also working to develop oral small molecule alpha-synuclein inhibitors, and anti-alpha-synuclein antibodies to treat Parkinson’s and related diseases.

The grant amount was not released.

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Alpha-Synuclein PET Tracers Identified with Potential to Track Parkinson’s Progression, AC Immune Says

alpha-synuclein PET tracers

Tracer compounds with high affinity and selectivity to alpha-synuclein deposits have been identified that could be used to detect and track Parkinson’s disease progression, AC Immune announced.

Findings were recently presented in the study, “Identification and Characterization of Selective and High Affinity Small Molecules for Positron Emission Tomography (PET) Imaging of Pathological Alpha-Synuclein,” during the 14th International Conference on Alzheimer’s and Parkinson’s Diseases and related neurological disorders (AD/PD 2019) in Lisbon, Portugal.

In the brains of Parkinson’s patients, there is a buildup of a protein called alpha-synuclein that forms clumps known as Lewy bodies, which are toxic and lead to neuronal death. Tau and beta-amyloid protein aggregates, commonly found in Alzheimer’s disease, are also known to play a role in Parkinson’s disease, but the exact mechanism remains elusive.

Clusters of misfolded alpha-synuclein proteins — meaning they are not in their correct structure — have been associated with disease severity.

There are noninvasive imaging techniques that allow researchers to visualize the metabolic processes in the body, such as the positron-emission tomography (PET) scan.

Developing new alpha-synuclein-specific PET tracers would allow scientists to study the distribution and the changes of the toxic clumps of alpha-synuclein protein as the disease progresses.

AC Immune screened its robust library of small molecules for suitable alpha-synuclein PET tracer candidates. This “molecular collection,” also known as the Morphomer platform, enables the identification of a new class of low molecular weight compounds, which, in turn, allows for the generation of small molecules — called morphomers — that specifically bind to misfolded proteins, working to break up the neurotoxic clusters and inhibit protein aggregation.

Researchers measured these molecules’ affinity to alpha-synuclein and selectivity over other protein aggregates (tau and beta-amyloid) in post-mortem samples from Parkinson’s and Alzheimer’s patients.

Several molecules exhibited high affinity, binding to alpha-synuclein present within neurons of Parkinson’s brain sections. These compounds were selective for alpha-synuclein aggregates over beta-amyloid and tau clusters.

Because a PET scan uses a small amount of a radioactive molecule, or tracer, to show differences between healthy tissue and diseased tissue, researchers radio-labeled these promising compounds with fluorine-18, a radioactive molecule.

They then evaluated these molecules’ ability to penetrate the brain as well their molecular fate within a living organism. Using non-human primates, they identified molecules with fast brain uptake and a rapid washout (meaning the biomolecule was rapidly eliminated from the body), which are the desired characteristics for a central nervous system PET tracer.

The identified alpha-synuclein PET tracer candidates will soon enter clinical trials for the imaging of pathological alpha-synuclein in Parkinson’s disease and other alpha-synuclein-related diseases.

“These data show the potential for what may be the first PET tracer for PD, which we are now moving into a Phase 1 trial,” Andrea Pfeifer, PhD, CEO of AC Immune SA, said in a press release.

“We believe that therapeutic developments coupled with the diagnostic tools needed to properly identify and select patients allow us to follow disease progression and confirm potential efficacy of therapeutic interventions. This will provide critical differentiation for our product-candidates and benefit patients with neurodegenerative diseases,” she added.

Besides these data on PET tracers, AC Immune and its partners presented six more studies on the potential role and discovery of other imaging tracers for Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), supranuclear palsy, and dementia.

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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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New PET Tracer with Potential to Diagnose Parkinson’s to Be Tested in First-in-Human Study

PET tracer

An innovative Positron Emission Tomography (PET) tracer that has the potential to diagnose Parkinson’s disease will soon be tested in humans for the first time.

Led by Switzerland-based AC Immune, which developed the technology, the study is expected to begin in the second half of 2018. The company recently presented the data on its new product at the AAT-AD/PDTM Focus Meeting 2018 in Turin, Italy.

“We are excited about this significant step in our development of potentially the first ever PET tracer for earlier and more accurate diagnosis of Parkinson’s,” Andrea Pfeifer, CEO of AC Immune, said in a press release. “This important milestone underlines our vision to become a global leader in precision medicine of neurodegenerative diseases, leveraging our proprietary technology platform.”

The company used its Morphomer platform, designed to interact with misfolded and aggregated proteins, to develop the PET tracer, which is highly selective for alpha-synuclein, enabling an earlier and more accurate Parkinson’s diagnosis.

AC Immune’s technology is aimed at not only detecting alpha-synuclein in patients, but also monitoring the effects of treatments targeting protein clumps. The research program has been spotting small molecules selective for alpha-synuclein and suitable for development as PET tracers.

Upon entering the brain, the new imaging agent, called a PET tracer, binds to abnormal or misfolded alpha-synuclein. Its radioactive label enables the imaging device to detect bound alpha-synuclein, informing clinicians on the amount and distribution of pathological brain alpha-synuclein.

If successful, the new PET tracer would be the first alpha-synuclein tracer to receive regulatory approval for commercial distribution. Its specificity would be important not only for Parkinson’s patients, but also for other disorders characterized by aggregated alpha-synuclein, collectively called synucleinopathies.

AC Immune has been collaborating with Biogen on this program since April 2016. The companies will proceed with the development and seek clinical validation for the use of the PET tracer as an imaging biomarker for Parkinson’s.

The Michael J. Fox Foundation for Parkinson’s Research (MJFF) is supporting this project. “We are very pleased about this next important step in the development of an alpha-synuclein imaging agent,” Jamie Eberling, PhD, director of research programs at MJFF, said.

“Having a PET tracer to detect and track Parkinson’s disease would be transformative for Parkinson’s research and patient care,” she said.

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Source: Parkinson's News Today