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Seelos Begins Animal Study Investigating SLS-007 as Parkinson’s Treatment

SLS-007 animal study

Seelos Therapeutics has begun a preclinical study in rodents to test a gene therapy approach to deliver its investigational candidate SLS-007, a potential treatment for Parkinson’s disease. Results are expected by late this year or early 2021.

One hallmark of Parkinson’s disease progression is the formation of Lewy bodies, abnormal protein clusters that form in brain cells and disrupt their regular function. These clusters are toxic to nerve cells and are thought to underly the development of Parkinson’s. A major component of Lewy bodies is the protein alpha-synuclein.

SLS-007, which was developed originally by a team of researchers at the University of California, Los Angeles, is a family of molecules, known as peptide blockers, that are designed to lessen alpha-synuclein aggregation.

Specifically, SLS-007 targets the non-amyloid core region of the alpha-synuclein protein, which is more prone to aggregation.

Previous, in vitro studies — experiments conducted outside of a live animal — showed that SLS-007 had the potential to block Lewy body formation by preventing the clustering of alpha-synuclein.

This was accomplished by preventing the propagation and seeding of alpha-synuclein, a process in which a small amount of the protein provides the template for the aggregation of normal protein into larger clusters, or clumps.

“In in vitro models, halting or slowing the aggregation of alpha synuclein dramatically slowed the formation of Lewy Bodies which are the hallmarks of the pathogenesis of Parkinson’s,” Raj Mehra, PhD, chairman and CEO of Seelos, said in a press release.

Having established the potential benefit of SLS-007 as a disruptor of Lewy body formation, the researchers now have begun to investigate the treatment in mice.

The team will use a transgenic mouse model that previously was designed to study the propagation of alpha synuclein. Researchers will test a modified, harmless form of a virus, called an adeno-associated virus (AAV1/AAV2), as a vehicle (or vector) to deliver SLS-007.

Two specific peptides that comprise SLS-007, called S62 and S71, have been tagged with a unique marker that will allow researchers to track their activity. Production of the AAV vectors already has been completed by Seelos.

Researchers will assess the ability of SLS-007 to protect dopaminergic neurons in these mice. The study also will determine the pharmacokinetics, pharmacodynamics, and target engagement of SLS-007 in mice.

(Pharmacokinetics refers to the movement of a medication within the body while pharmacodynamics refers to the interactions between the body and a compound.)

Research on SLS-007 will augment Seelos’ ongoing studies of SLS-004, an investigational gene therapy that uses another harmless virus, called a lentivirus, to deliver an enzyme called DNA methyltransferase 3A that is thought to limit the production of alpha-synuclein.

“This program [SLS-007] should complement SLS-004 in which we also recently began studies,” said Mehra.

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Results Set Stage for Phase 2 Trial of Investigational Vaccine Affitope PD01A, Affiris Says

Affitope PD01A vaccine

Multiple administrations of Affitope PD01A, an investigational vaccine for Parkinson’s disease, elicit a safe and sustained immune response against alpha-synuclein — a protein involved in the development of Parkinson’s — in patients at the early stages of the disease, according to results from a Phase 1 clinical program.

Trial findings were reported in the study, “Safety and immunogenicity of the α-synuclein active immunotherapeutic PD01A in patients with Parkinson’s disease: a randomised, single-blinded, phase 1 trial,” published in The Lancet Neurology.

A distinctive feature of Parkinson’s is the progressive degeneration of brain cells due to the accumulation of toxic clumps of the protein alpha-synuclein, called Lewy bodies.

Affitope PD01A is an experimental vaccine being developed by Austrian biotech company Affiris to treat Parkinson’s. It works by prompting a patients’ immune system to produce antibodies against a man-made peptide that is very similar to alpha-synuclein.

Preclinical studies in two mouse models of Parkinson’s have shown that Affitope PD01A lowered the number of alpha-synuclein aggregates found in the animals’ brains, improved their memory, and alleviated motor impairments.

Based on these promising findings, Affitope PD01A advanced to clinical testing in a Phase 1 clinical program.

The clinical program consisted of the first-in-human randomized Phase 1 trial of Affitope PD01A (NCT01568099), followed by three extension studies (NCT01885494; NCT02216188; NCT02618941).

During the first trial, patients aged 45–65 with early-stage Parkinson’s were assigned randomly to receive four under-the-skin (subcutaneous) injections of Affitope PD01A at a dose of 15 or 75 micrograms (mcg) on their upper arm, once every four weeks.

Study participants then were enrolled in the first extension study and initially monitored for a period of 52 weeks (approximately one year), followed by an additional period of 39 weeks (approximately 10 months).

After that, patients were divided randomly into two dose groups (15 or 75 mcg) to receive the first booster vaccine immunization, and followed for 24 weeks (six months). All patients received a second booster immunization of Affitope PD01A at a dose of 75 mcg and were monitored for an additional 52 weeks.

Of note, a booster is an extra administration of a vaccine after the first exposure dose, which allows the body to increase its immunity when the initial vaccine starts to wear off.

Researchers now reported the findings of the entire Phase 1 clinical program of Affitope PD01A.

A total of 32 patients with early Parkinson’s were recruited from February  2012 to February 2013 to participate in the first Phase 1 trial of Affitope PD01A. From these, 24 were eligible to participate in the study, and were assigned randomly to one of the two dose groups to receive four immunizations of the vaccine.

Three patients withdrew from the program, and the remaining 21 (87%) received all six vaccine immunizations.

Repeated administrations of Affitope PD01A led to a significant increase in the levels of antibodies targeting alpha-synuclein, which reached a maximum value at week 12, after patients had received three immunizations.

This increase in the levels of antibodies against alpha-synuclein allowed the patients’ immune system to mount a specific immune response against the protein.

In patients receiving the highest dose of the vaccine, the levels of alpha-synuclein aggregates found on their cerebrospinal fluid (CSF, the fluid that surrounds the brain and spinal cord) dropped by 51%, confirming successful target engagement of the newly formed antibodies to alpha-synuclein.

Antibody levels began to drop over the first two years of the program, but rapidly rose in response to booster immunizations, confirming the first vaccine administrations successfully imprinted a memory effect in the patients’ immune systems. This allowed patients to maintain a continuous immune response against alpha-synuclein until the end of the program.

Repeated vaccine immunizations also were found to be safe and well-tolerated over the entire duration of the program.

All patients experienced at least one adverse event (side effect) during the trials, but most of them were found to be unrelated to treatment. None of the study participants discontinued treatment due to adverse events.

The most common treatment-related adverse events included fatigue, headaches, muscle pain, muscle rigidity, and tremor.

“The PD01A safety profile and the substantial sustained aSyn [alpha-synuclein] antibody response targeting both the toxic oligomeric and fibrillar form of aSyn, which are believed to contribute to the pathology of PD [Parkinson’s disease], may offer a promising strategy for long-term management of PD, addressing an urgent medical need,” Dieter Volc, MD, said in a press release. Volc is principal investigator of the study series and head of the Parkinson Center at the Privatklinik Confraternitaet, Vienna.

“The safety profile and positive antibody response of PD01A supports the further development of this immunotherapeutic for the treatment of Parkinson’s disease in a phase 2 clinical trial,” the researchers wrote.

The company expects to start the Phase 2 trial later this year.

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Fox Foundation Grant to Find Protein Biomarkers for Early Diagnosis

biomarkers

Erisyon, a biotechnology company specializing in the study of proteins, was awarded a grant by The Michael J. Fox Foundation (MJFF) to find and validate potential markers of Parkinson’s disease in its early stages.

The grant, reported to be worth $189,000, will go toward deploying single-molecule protein sequencing to detect and validate protein biomarkers that might inform an early diagnosis. The earlier a person is diagnosed, the sooner treatment can begin.

“Our single-molecule assay will help untangle the mysteries of using alpha-synuclein as a potential biomarker,” Talli Somekh, the company’s CEO, said in a press release. “This technology can help to identify the smaller aggregate proteins that cause Parkinson’s before they form large, insoluble particles in the brain.

“With the support of The Michael J. Fox Foundation, our study aims to quantify very accurately the biomarker for Parkinson’s at a much earlier stage of the disease,” Somekh added.

A Parkinson’s hallmark is the misfolding of the alpha-synuclein protein, which promotes its aggregation into clumps that are deadly to dopamine-producing nerve cells. These cells are responsible for releasing the neurotransmitter dopamine, which is critical for regulating brain cell activity and function.

Focused on personalized medicine and treatment discoveries through a better understanding of proteins, Erisyon aims to commercialize the first single-molecule protein sequencer to upend how disease is detected, treated, and monitored.

A 2018 study into the company’s proprietary new way of sequencing proteins showed the method was more sensitive than existing technology, identifying individual protein molecules instead of requiring millions of molecules at a time. The hope is that this technology — developed by researchers at the University of Texas at Austin — will make it easier to uncover diagnostic biomarkers for Parkinson’s and other diseases, and broaden understanding of how cells function.

Next-generation technology has made sequencing the entire genome of any living organism swift, affordable, and accurate, accelerating biological research. The new technology offers quick and comprehensive information about millions of proteins that play a role in disease and in the normal functioning of cells.

In many disorders, including Parkinson’s, cells produce proteins and other substances that act as unique biomarkers. Better detection of these biomarkers would help scientists understand what causes disorders such as Parkinson’s, allowing more accurate, earlier diagnoses. Molecular biomarkers are gauges that provide insights into a patients’ health, and are key indicators of disease progression and companion diagnostics.

The scientific standard for sequencing proteins is a tool called mass spectrometry, which can detect a protein if there are about a million copies of it. As such, it can be insufficiently sensitive for many applications. Mass spectrometry also it has what is called a low throughput, meaning it can detect only a few thousand distinct protein types in a single sample.

Erisyon reports that its technology, with its single-molecule sensitivity, can isolate and measure blood serum-based biomarkers whose concentrations are below the sensitivity of existing techniques. It also has a high-throughput, being able to measure at least one billion individual proteins in a single sample.

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Changes in Structure of Alpha-synuclein Seen to Make Protein Prone to Clumping

protein clumps and disease

Structural changes within alpha-synuclein can make this protein more prone to clumping — a common feature of Parkinson’s — a research group found, a discovery that might lead to ways of stopping this disease in its early stages.

The study, “Extent of N-terminus exposure of monomeric alpha-synuclein determines its aggregation propensity,” was published in the journal Nature Communications.

A hallmark of Parkinson’s disease is the misfolding of the alpha-synuclein protein, which promotes its aggregation into clumps that are deadly to dopamine-producing nerve cells. These cells are responsible for releasing the neurotransmitter dopamine, which is critical for regulating brain cell activity and function.

Alpha-synuclein has a variety of conformational states that are constantly reconfiguring, depending on environmental cues. But exactly which conformations are prone to aggregation, and how mutations influence these different shapes is not known.

Researchers at the University of Cambridge set out to identify aggregation-prone conformations, and the environmental factors that destabilize non-aggregation prone conformations, leading them to favor clumping.

A better understanding, they suggest, could aid in developing therapies that stabilize the native alpha-synuclein in Parkinson’s and other diseases characterized by the buildup of toxic alpha-synuclein aggregates (synucleinopathies).

“We wanted to understand why the normally healthy, monomeric [single protein chains] and soluble aSyn [alpha-synuclein] suddenly starts to misfold,” Amberley Stephens, with the university’s Department of Chemical Engineering and Biotechnology and the study’s co-first author, said in a press release.

However, “this is made very difficult because aSyn has no true structure but exists as lots of intermediate structures or conformations that are highly dynamic,”­­ Stephens said.

Researchers compared the initial conformation of a normal alpha-synuclein, one not prone to forming aggregates, to mutated forms of this protein that are more or less prone to clumping than is the normal protein. Mutations in the alpha-synuclein coding gene SNCA are often seen in familial cases of Parkinson’s.

Using tools developed at the University of Exeter, the proteins’ structure and dynamics were assessed in the presence of calcium, known to induce aggregation.

“Our collaborators at the University of Exeter have been working on instrument development, so that we are able to detect smaller and smaller differences between protein populations — this is particularly important for such a flexible protein like aSyn,” said Maria Zacharopoulou, the study’s other co-first author.

The N-terminus of alpha-synuclein, which is essentially the first part of the protein sequence, was found to be mostly responsible for the differences in susceptibility to aggregation. If this N-terminus had a conformation making it more exposed to its surroundings, the protein would open in the presence of calcium, turning it more prone to aggregation.

The more exposed this first part of the protein was, the faster it would also aggregate. In contrast, less exposed or “closed” structures were less prone to form clumps.

Overall, these findings shed light on early steps in the formation of toxic alpha-synuclein aggregates.

“We conclude that the perturbation of long-range interactions upon calcium binding to monomeric aSyn leads to an increase in N-terminus solvent exposure for some aSyn variants which correlates with their increased aggregation propensity,” the researchers wrote.

This work may aid in the discovery of treatment approaches that stabilize alpha-synuclein, preventing it from acquiring aggregation-prone configurations. Likewise, they might be able to convert clumping-prone protein structures into normal ones.

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Preclinical Study of SLS-004, Potential Parkinson’s Gene Therapy, Starting

gene therapy study

Seelos Therapeutics announced it is beginning, earlier than expected, a preclinical study into its investigational gene therapy candidate for Parkinson’s disease called SLS-004.

The exact nature of this early research work was not detailed in a press release.

Nerve cell damage in Parkinson’s is caused by the buildup of toxic forms of the alpha-synuclein protein, and resulting clumps of misfolded proteins known as Lewy bodies. These toxic aggregates damage and eventually kill nerve cells — called dopaminergic neurons — in a region of the brain that regulates muscle movement and coordination.

The loss of these nerve cells leads to a shortage of dopamine, a neurotransmitter (chemical messenger) that allows nerve cells to communicate and helps to regulate movement.

Seelos reports that SLS-004 uses a modified, harmless form of a virus, known as a lentivirus, to deliver an enzyme called DNA methyltransferase 3A to promote the methylation of a particular region of the gene coding for alpha-synuclein, called SCNA.

Methylation — the addition of specific chemical (methyl) groups that sit on top of a particular region within DNA — is a way to regulate the activity of a gene mainly by “switching” it off.

This system is based on CRISPR-dCas9 gene editing technology, and intends to fine-tune the activity of the SNCA gene to lower the production of alpha-synuclein.

“There has been a high level of interest in the alpha-synuclein approach to Parkinson’s and beginning further work on our first gene therapy program is exciting,” Raj Mehra, PhD, chairman and CEO of Seelos, said in the release.

“Initiating this preclinical study earlier than expected is also very significant,” he added.

Earlier preclinical studies investigated SLS-004’s efficacy when delivered to dopaminergic neurons derived from stem cells donated by a Parkinson’s patient. Results showed that the gene therapy effectively altered the activity of the SCNA gene, leading to a lower levels of alpha-synuclein.

It also was seen to possibly protect against disease-related changes, including the production of harmful reactive oxygen species (ROS), and to improve cell viability.

Seelos is also testing SLS-007, another Parkinson’s gene therapy candidate that aims to lessen the aggregation of alpha-synuclein in patients.

SLS-007 is made of a family of peptide blockers that specifically target a central region of alpha-synuclein, called the non-amyloid component core, that is particularly prone to aggregation.

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Nitrome Raises $38M to Bring Potential Enzyme Treatment into Clinical Trials

neuron replacement therapy

Nitrome Biosciences has raised $38 million in Series A financing to advance its lead program toward clinical trials for Parkinson’s disease (PD) and other age-related disorders.

“This financing will enable Nitrome to advance our mission of impacting the lives of patients with neurodegenerative and other age-related diseases,” said Irene Griswold-Prenner, PhD, Nitrome founder and CEO, in a press release.

Nitrome’s therapies targeting Parkinson’s aim to inhibiting a newly identified enzyme the company calls synuclein nitrase. According to the company, this enzyme causes or speeds the nitration — a type of chemical modification caused by cellular stress — and buildup of alpha-synuclein, a PD hallmark. Nitrome hopes to evaluate in a pilot study whether blocking or impeding this enzyme might slow or halt Parkinson’s progression.

Aggregation of alpha-synuclein — the main component of PD Lewy bodies — is found in the brain as well as the peripheral autonomic nervous system, which ultimately impacts breathing and digestion.

A nitrated form of the protein can be detected in salivary gland tissue of Parkinson’s patients. Since nitrated alpha-synuclein is present in early disease stages, it has the potential to be a promising disease biomarker.

Nitrome is also seeking to expand application of its platform technology to other age-related diseases, like diabetes, heart disease, and cancer.

“Nitrome’s breakthrough science is paving the way for novel, disease-modifying therapies, said Henrijette Richter, PhD, a  managing partner of Sofinnova Partners and a new Nitrome board member. “Nitrome’s team is made up of highly respected neuroscientists accomplished in drug discovery. The company is well-positioned to potentially transform the lives of Parkinson’s patients and others who suffer from age-related diseases.”

The funding was co-led by Sofinnova and AbbVie Ventures, and included the Dementia Discovery Fund, Mission Bay Capital, and Alexandria Venture Investments.

The Michael J. Fox Foundation for Parkinson’s Research awarded Nitrome a Target Advancement grant of an undisclosed amount in June 2019 to help support further development of potential PD therapies.

Roughly 7 million to 10 million individuals globally have Parkinson’s disease, including some 1 million in the United States.

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Immune Cells in Blood May Help with Diagnosis Years Before Motor Onset

immune cells

Immune cells targeting the alpha-synuclein protein are common in Parkinson’s patients, and new research shows that these cells can be present in the blood up to 10 years before diagnosis, long before disease symptoms are evident.

This finding carries important implications for people at risk, such as those carrying genetic factors associated with Parkinson’s or displaying pre-motor symptoms. They may benefit from immunotherapies that prevent these immune cells from further damaging neurons.

The study, “α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease,” was published in Nature Communications.

Decades before a definitive diagnosis, before symptoms are present, people with Parkinson’s start showing molecular changes in the body that are followed by such non-motor symptoms as difficulty sleeping, constipation, mood changes, and loss of a sense of smell.

These changes are usually not enough to diagnose the disease — that is usually done only when motor symptoms of Parkinson’s are evident. But at that time, a large proportion of dopaminergic neurons — those that produce dopamine — have already been irreversibly lost, limiting the effectiveness of treatment.

Researchers are trying to identify early changes in Parkinson’s patients that can help in a definitive diagnosis before extensive nerve cell damage has taken place.

“Once these cells are gone, they’re gone. So if you are able to diagnose the disease as early as possible, it could make a huge difference,” Cecilia Lindestam Arlehamn, PhD, the study’s first author, said in a press release.

A team led by David Sulzer, PhD, at Columbia University Medical Center, and Alessandro Sette, at La Jolla Institute for Allergy and Immunology, reported in a 2017 study that some Parkinson’s patients have immune T-cells that react against the alpha-synuclein protein, known to form toxic clumps in dopamine-producing neurons of Parkinson’s patients.

This was the first direct evidence that autoimmunity could contribute to Parkinson’s development, with some immune T-cells mistakenly attacking nerve cells.

To understand how these cells were contributing to the disease, the team now set out to explore how these immune cells changed over time, both before and after diagnosis.

Researchers first examined blood samples from a single patient spanning 11 years prior to his Parkinson’s diagnosis, and then nine years after diagnosis. Each year, the patient underwent two blood collections, one in March and another in September.

They found that T-cells reacting against alpha-synuclein were detectable 10 years before the diagnosis and start of motor symptoms, reached a peak shortly before disease onset, and then declined in the years that followed.

Sulzer and Sette then collaborated with a team at the University of Alabama at Birmingham to examine how alpha-synuclein immune responses in blood samples from a group of Parkinson’s patients compared to age-matched healthy individuals serving as controls.

Regardless of time from diagnosis, patients overall exhibited significantly stronger responses (T-cell reactivity) to alpha-synuclein than controls. This response also appeared to be specific to Parkinson’s, as a group of Alzheimer’s disease patients showed a reactivity to alpha-synuclein similar to controls.

As noted in the first patient, these Parkinson’s patients also showed stronger reactivity responses closer to their diagnosis, which then weaned over time. In a group of 96 patients, about 40% of those diagnosed within 10 years had such strong responses, compared with 8.6% of those diagnosed more than 10 years ago.

An analysis of the pro-inflammatory molecules being produced in response to alpha-synuclein allowed the researchers to identify CD4-positive T-cells as the main players in this immune response. These immune cells do not directly neutralize a threat, instead they trigger other cells of the immune system to fight it.

In addition to a shorter time since diagnosis, older age and low doses of levodopa were also associated with increased responses to alpha-synuclein. Together, these three factors best identified patients with immune responses, though its sensitivity (or true positive rate) was still low.

“In conclusion, the present study confirms an association of [alpha-synuclein]-specific T cells and PD [Parkinson’s disease], and demonstrates that the presence of these T cells is a feature of preclinical and early motor PD,” the researchers wrote.

“This tells us that detection of T cell responses could help in the diagnosis of people at risk or in early stages of disease development, when many of the symptoms have not been detected yet,” Sette said.

These findings suggest that monitoring immune reactivity against alpha-synuclein may help to identify quickly those in need of preventive treatments that stop or delay nerve cell degeneration in earlier stages of disease.

Such treatments, like anti-TNF therapies, have already been associated with a lower incidence of Parkinson’s.

“Importantly, we could dream of a scenario where early interference with T cell responses could prevent the disease from manifesting itself or progressing,” Sette added.

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Patients in Trial of Potential DMT Ably Capture Early Parkinson’s, Roche Says

Parkinson's trial update

Roche presented initial data from an ongoing Phase 2 clinical trial evaluating prasinezumab (PRX002/RG7935) — an antibody against the alpha-synuclein protein — in more than 300 people with early stage Parkinson’s disease.

Data highlighted that the trial’s participants, including those on MAO-B inhibitors, represent a wider population of patients and one appropriate to studying the effects of disease modifying therapies, such as prasinezumab, on Parkinson’s progression.

Given at the Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting (AAT-AD/PD), held virtually on April 2–5, the oral presentation is titled “A Phase 2 study to evaluate the safety and efficacy of prasinezumab in early Parkinson’s disease (PASADENA): Rationale, design and baseline data.”

Alpha-synuclein is a protein found mainly in nerve cells (neurons) and thought to be involved in neuronal communication.

In Parkinson’s disease, toxic forms of alpha-synuclein form clumps — known as amyloid, or Lewy bodies — that contribute to the disease onset and progression. Evidence also suggests that these toxic aggregates can propagate, spreading to nearby neurons and resulting in progressive neurodegeneration.

Treatments able to lessen alpha-synuclein accumulation are likely to beneficially alter the course of Parkinson’s disease.

Prasinezumab, developed by Prothena in collaboration with Roche, is an injectable monoclonal antibody designed to selectively bind to alpha-synuclein aggregates, promoting an immune reaction against them.

By clearing alpha-synuclein clumps, prasinezumab is thought to slow neurodegeneration associated with the protein’s toxic accumulation and its transmission to neighboring neurons.

In animal models of alpha-synuclein-related disease, prasinezumab reduced the accumulation of the protein’s toxic clumps, protected neuronal communication, and halted a worsening in behavioral symptoms.

A multiple-ascending dose Phase 1b study (NCT02157714) in 80 Parkinson’s patients showed that the therapy was safe and well-tolerated, and that it sustainably lowered blood levels of alpha-synuclein by up to 97% after a single injection.

These results supported the start of the current Roche-sponsored, two-part Phase 2 study, called PASADENA (NCT03100149). The trial is evaluating the safety and effectiveness of prasinezumab in 316 patients with early stage Parkinson’s (two or fewer years since diagnosis).

Participants — who had no prior disease modifying treatment or were being treated with MAO-B inhibitors — were recruited at 65 clinical sites across the U.S., France, Germany, Austria, and Spain.

In the first part, patients were randomly assigned to an intravenous (into the vein) infusion of one of two doses of prasinezumab (1500 mg or 4500/3500 mg, depending on body weight), or of a placebo, once every four weeks for one year.

Those finishing this first part were eligible to enter the trial’s ongoing second part, a one-year extension in which all are either continuing treatment or switching to one of the two treatment doses from placebo. Doses given in this second part reminded blinded, and treatment will be followed by 12 weeks of follow-up.

PASADENA’s main goal is to assess whether prasinezumab is superior to a placebo in lessening motor and non-motor symptoms — measured by the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) total score — after one year (at the completion of part one).

Secondary goals include clinical and patient-based effectiveness measures, as well as safety measures. The level of neurodegeneration of dopamine-producing neurons will also be evaluated using a brain imaging tool called Dopamine Transporter Single Photon Emission Computed Tomography (DaT SPECT).

Roche’s PD Mobile Application v2. — a smartphone app that includes several motor function tests, to be performed every other day, and passive monitoring — is also being used as an exploratory measure of patients’ motor abilities.

Roche in its online session presented  baseline (study’s start) data on PASADENA’s participants, compared to data of a reference patient population — the Parkinson’s Progression Markers Initiative (PPMI), an observational, international clinical study to establish Parkinson’s biomarkers.

In PASADENA, participants’ mean age was 59.9 years and all had lived with the disease for a mean of 10.1 months. Most were men (67.4%) and were treatment-naive (63.6 %), meaning they had no prior treatments.

Those using MAO-B inhibitors were slightly younger and had been diagnosed with Parkinson’s for a slightly longer time than treatment-naive patients.

Overall, the patients in PASADENA were mostly classified as stage two (75.3%) on the Hoehn and Yahr scale, with only 24.7% of participants classified as stage one. This scale measures disease progression, with stage one being the earliest, with mild symptoms evident on one side of the body, and associated with minimal or no functional impairment. Stage two, while still early, represents symptoms like rigidity or slowness evident on both body sides or at midline, and can includes changes in speech. Stage five is an advanced disease state.

Compared with the PPMI study population, patients enrolled in PASADENA have a longer mean disease duration (by about three to six months), a higher proportion are classified as stage two on the Hoehn and Yahr scale, similar motor symptom severity, and slightly milder non-motor symptoms.

They also showed a less pronounced loss of dopamine-producing neurons than those in the PPMI study.

“The PASADENA population can be considered representative of a wider [Parkinson’s disease] population and therefore suitable for testing the potential beneficial effect of [therapies] acting on disease progression, such as prasinezumab,” the researchers wrote.

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‘Microsteretcher’ Technique May Advance Parkinson’s Research

microstretcher technique

Researchers have developed a way to closely study the function of a cell’s transportation network, made up of structures called microtubules, that appears to be impaired in people with Parkinson’s disease.

This technique, called “microstretcher,” may help to better understand microtubules’ deficits and their underlying causes in Parkinson’s, as well as to identify new therapeutic targets.

“Our experimental set-up enables us to study the relationship between the deformation of microtubules and their biological functions,” Akira Kakugo, PhD, the study’s senior author at Hokkaido University, in Japan, said in a press release.

The new method was described in the study, “Regulation of Biomolecular-Motor-Driven Cargo Transport by Microtubules under Mechanical Stress,” published in the journal ACS Applied Bio Materials.

Microtubules are hollow tubular structures that provide structure not only to cells, but also form highways to transport molecules and organelles inside cells. This transport is mediated by motor proteins, namely dynein and kinesin, which move in opposite directions along microtubules’ “tracks.”

In nerve cells, microtubules are particularly involved in the transport of vesicles filled with neurotransmitters (chemical messengers used in nerve cell communication) down the axon, or nerve cell fiber, to be released as signals to other nerve cells.

Increasing evidence suggests that defective regulation of microtubules may have a role in the development of a broad range of neurodevelopmental, psychiatric, and neurodegenerative diseases, including Parkinson’s.

Microtubule dysfunction was shown to precede axon transport deficits and death of dopamine-producing nerve cells — a hallmark of Parkinson’s disease. In addition, several Parkinson’s-associated proteins, such as tau, alpha-synuclein, parkinpink1, and LRRK2 regulate or appear to affect microtubule stability.

However, there was no experimental set-up to properly study the transport process in microtubules and the effects of disturbances in that process, until now.

Researchers at Hokkaido University and the National Institute of Information and Communications Technology, in Japan, developed a unique technique to control microtubular physical deformation and observe its effects on their transport function.

The microstretcher consists of a horizontal plate with flexible medium inside, which can be “stretched” or “compressed” using a computer system.

The team first used specific proteins to attach microtubules to the pre-stretched medium in a way that the microtubules lied parallel to the surface area and “stretching” axis. Next, dyneins bound to a fluorescent cargo were added to the microtubules.

With this system, researchers were able to evaluate the effects of stretching and compressing the flexible medium, and consequently straightening and bending the microtubules, in dynein-associated transport.

Results showed that the dynein-cargo moved faster as the microtubules began to bend, but only until the compressive strain reached about 25%, “beyond which the dynein-driven transport is retarded,” the researchers wrote.

From that point onward, the speed of dynein-associated transport started to decrease and eventually the deformation led to microtubule collapse and no dynein movement. Different speeds of motion also were observed along distinct areas of the bended microtubules.

The team noted that dynein’s faster motion in slightly bended, rather than straight, microtubules may be associated with the protein’s “walking-like” movement. Also, they believe these physical characteristics of microtubules may contribute to their functions in regulating many cellular processes.

“This work offers a technical advantage for a systematic study of the correlation between the deformation of MTs [microtubules] and its biological functions, i.e., cargo transport, as well as an opportunity to explore the interaction of deformed MTs with MT-associated proteins such as (…) tau,” the researchers wrote.

This new technique is “expected to help explain the [underlying disease-associated mechanisms] of traumatic brain injury, which mechanically stresses cells, and neurological conditions like Huntington’s and Parkinson’s diseases, in which microtubules are known to malfunction,” said Syeda Rubaiya Nasrin, the study’s first author.

Next, the team hopes to evaluate the effects of microtubule physical deformation in kinesin-driven transport along their “tracks.”

“The more we understand this process, the closer we might get to designing new nature-inspired materials that can act in a similar way,” Kakugo said.

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APOE Variant Directly Tied to Lewy Body Dementias in 2 Studies

APOE4 study

A variant of the apolipoprotein (APOE) protein, called APOE4, has been shown to directly affect Lewy body dementias, such as Parkinson’s disease.

Two separate studies, published simultaneously, found that APOE4 directly regulates levels of alpha-synuclein, which clumps  to form the nerve-damaging Lewy bodies that are the main culprits of the nerve cell death that defines Parkinson’s.

Their combined results help in understanding how APOE4 works, and how it affects disease progression. Greater insights into these mechanisms are vital for advancing research into treatments for Lewy body dementias.

Published in the peer-reviewed journal Science Translational Medicine, the two studies are “APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid,” and “APOE genotype regulates pathology and disease progression in synucleinopathy.”

“It’s nice when you do science separately … but reach similar conclusions,” Guojun Bu, PhD, senior author of one study and chair of neuroscience at the Mayo Clinic, said in a news release published in Neurology Today.

APOE4 has been the focus of research into both Alzheimer’s and Parkinson’s for some time. Studies have shown that it strongly associates with these diseases, and that it plays a strong functional role in the accumulation of amyloid-beta and tau within neurons.

Whether APOE4 directly promotes alpha-synuclein aggregation or affects disease progression as a result of these aggregates, however, is not known.

In each of these studies, scientists engineered mice to express one of three APO variants — E2, E3, or E4 — or to have no APOE at all (knockout mice). They then used different methods to examine associations between the APOE variants and disease features, or pathology.

Albert Davis, an assistant professor of neurology at Washington University School of Medicine in St. Louis and colleagues monitored one group of each type of mice, looking for the development of alpha-synuclein aggregates. His group injected groups of each of these engineered mice with alpha-synuclein fibrils to induce protein clumping, and see how its spread varied in each genetic background.

Among the first group, those expressing APOE4 (E4) showed higher amounts of insoluble and phosphorylated (pathologic) alpha-synuclein, and evidence of reactive gliosis — a type of neuroinflammation — than did mice in other groups.

Reactive gliosis refers to inflammation of glial cells, a class of protective neurons that include microglia, a cell often seen to be damaged in Parkinson’s. This inflammation typically occurs in response to damage to the central nervous system (CNS), such as the formation of Lewy bodies.

Mice carrying the E2 variant survived longer and did not show the motor difficulties seen in the other mouse groups.

Among mice injected with alpha-synuclein fibrils to monitor its spread throughout the brain, the E4 mice showed the greatest signs of pathology within the substantia nigra, the brain region most affected by alpha-synuclein aggregates in Parkinson’s.

This finding closely matched that of another recent paper, which concluded that microglia play “an integral role in the propagation and spread of alpha-synuclein pathology.”

The two papers reached different conclusions, however, regarding the order of events in inflammation and alpha-synuclein/Lewy body formation. While Davis’s group concluded that alpha-synuclein pathology leads to an inflammatory response, the other research group, lead by Jeffrey Kordower of Rush University, concluded that inflammation came first and played a driving role in alpha-synuclein aggregation.

“We and others in the field are going to look closely at that and follow up,” Davis said in the release.

Davis’ group also examined the genetic background of two groups of Parkinson’s patients, as a comparison to the mouse models. His group found people that in both cohorts, those with two copies of the E4 variant, showed the fastest cognitive declines.

“Our results demonstrate that APOE genotype directly regulates alpha-synuclein pathology independent of its established effects on [beta amyloid] and tau, corroborate the finding that APOE e4 exacerbates pathology, and suggest that APOE e2 may protect against alpha-synuclein aggregation and neurodegeneration in synucleinopathies,” these researchers concluded in their paper.

In the second study, led by Bu at the Mayo Clinic, mice were injected with viruses carrying different APOE variants.

Similar to Davis’ study, Bu’s group found that mice expressing E4, but not E2 or E3, showed more alpha-synuclein pathology and Parkinson’s-related symptoms, such as impaired behavior and the loss of neurons and synapses (the junctions between neurons where information is passed from one nerve cell to another). The E4 mice also showed deficits in their fat and energy metabolism.

Gu and his colleagues examined the brains of patients with Lewy body dementia, and discovered that those who had the APOE4 variant also showed greater alpha-synuclein pathology.

Eric Reimann, the executive director of Banner Alzheimer Institute, praised the studies, while adding that their results need to be confirmed in larger groups of both Parkinson’s patients, “including those without comorbid (simultaneously occurring) Alzheimer’s disease,” and healthy controls.

When two or more medical co-existing conditions can be common, telling the effects of one apart from the other is challenging. This is especially the case in disorders such as Parkinson’s and Alzheimer’s, which share many of the same disease features.

Reiman had also found the E4 variant to associate with higher odds for Lewy body dementia. In contrast to Davis’ study, however, Reiman found no link between the E2 variant and a lower disease risk.

Alice Chen-Plotkin, an associate professor of neurology at the University of Pennsylvania Perelman School of Medicine, commented in the release that “the data for E4 being bad is much stronger than for E2 being good.”

Although she expressed surprise at the strength of the effect Davis’s group found APOE4 to have on glial cells, she noted that researchers are coming to think much more about these nervous system support cells.

An ongoing Phase 2 clinical trial (NCT04154072), for instance, seeks to improve Parkinson’s outcomes by blocking glial activation and inflammatory signaling. At the same time, the National Institutes of Health (NIH) recently awarded a $4.8 million grant to study how APOE4 induces neurodegeneration.

The E2 variant is also the focus of an ongoing Phase 1 gene therapy trial (NCT03634007), seeking to deliver this protein to patients’ CNS as a way of treating Alzheimer’s disease.

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