Posts

Top 10 Parkinson’s Stories of 2018

Top 10, Parkinson's

Parkinson’s News Today provided you with daily coverage of important findings, treatment developments, and clinical trials related to Parkinson’s during 2018.

We look forward to bringing more news to Parkinson’s patients, as well as their family members and caregivers, during 2019.

Here are the Top 10 most-read articles of 2018, with a brief description of what made them interesting to the Parkinson’s community.

 No. 10 – “Phase 2 Trial Shows Nilotinib Potential to Modulate Dopamine in Parkinson’s

Results of a Phase 2 trial (NCT02954978) of Novartis’ nilotinib in 75 patients with mid-stage Parkinson’s and mild cognitive impairment suggested the therapy increased production and metabolism of dopamine within one to four hours after a single treatment. Also, low-dose nilotinib (150 mg and 200 mg) — marketed as Tasigna for certain types of leukemia — was associated with lower levels of an altered and toxic form of alpha-synuclein, the main component of Parkinson’s hallmark protein clumps known as Lewy bodies.

No. 9 – “Potential Parkinson’s Vaccine, Affitope PD01A, Safe and Possibly Effective in Long-term, Phase 1 Trial Series Finds

The long-term safety, tolerability, and immune response associated with an experimental vaccine called Affitope PD01A were studied in a series of four consecutive Phase 1 trials: AFF008 (NCT01568099), AFF008E (NCT01885494), AFF008A (NCT02216188), and AFF008AA (NCT02618941). Twenty-one treated and five control patients completed the series. The results showed that both 15 μg or 75 μg doses of Affitope were well-tolerated, only causing mild injection-site reactions. The vaccine, being developed by Affiris, induced a clear immune response against its target — alpha-synuclein — that was stabilized with “boost” injections. At week 26 of treatment, it induced a trend toward lower levels of a toxic form of alpha-synuclein in the blood and cerebrospinal fluid, the liquid surrounding the brain and the spinal cord.

No.8 – “MRI-Focused Ultrasound Undergoing Phase 3 Clinical Trial for Parkinson’s Treatment

A Phase 3 trial (NCT03319485) of a potential nonsurgical treatment, known as magnetic resonance imaging (MRI)-guided focused ultrasound, also attracted significant interest. The InSightec-sponsored study — still recruiting patients with advanced disease — is exploring the procedure’s safety and effectiveness. It follows a pilot trial demonstrating lesser upper-limb tremors in patients with tremor-dominant Parkinson’s who did not respond to other therapies. In this non-invasive approach, ultrasound waves destroy damaged tissue in a brain structure called the globus pallidus, which is involved in the regulation of voluntary movement. The team expects to enroll 80 to 100 participants.

No. 7 – “Key to Effective Parkinson’s Treatment May Lie in Stem Cells, Researchers Say

Advancements in stem cell therapy for Parkinson’s were also of clear interest to our readers. Two articles assessed the replacement of dopamine-producing neurons, progressively lost during the course of disease. The first focused on patient-derived induced pluripotent stem cells (iPSCs), fully matured cells that researchers are able to reprogram in vitro (in the laboratory) to revert them to a stem cell state in which they are able to grow into any type of cell, including dopaminergic nerve cells. The second study focused on an alternative approach to stem cell therapy that, instead of iPSCs, uses parthenogenetic-derived neural stem cells. These cells are obtained by chemical manipulations in unfertilized human oocytes, or immature egg cells, which are also able to grow into neurons. A Phase 1 trial (NCT02452723) of this approach is underway in patients with moderate to severe disease at a single site in Australia.

No. 6  “Psychosis in Parkinson’s Linked to Volume Changes in Specific Area of Brain, Study Says

Atrophy, or shrinkage, of the hippocampus — a critical brain area involved in memory — correlates with psychosis in patients with Parkinson’s disease. Specifically, researchers found that the volume of distinct subzones of the hippocampus was associated with psychosis severity and impaired cognitive functions. Greater volume was also seen in another specific brain area, the hippocampal fissure, and seems to correlate with poorer visual memory and visuospatial functions. Previous data had suggested that change in this area is a radiological hallmark of ongoing brain atrophy in the hippocampus.

No. 5 – Tiny Brain Bleeds Associated with Parkinson’s Disease Dementia, Study Reports

The link between tiny bleeds in the brain — cerebral microbleeds (CBMs) — with both cognitive impairment in Parkinson’s disease and risk of associated dementia was No. 5 among the year’s most-read stories. CBMs are small (2-10 mm as assessed by MRI), chronic brain hemorrhages believed to be caused by structural abnormalities of the brain’s small vessels. Scientists found that CBMs were more common in Parkinson’s patients with dementia than in those without dementia, and were associated with lower cognitive scores. Other findings showed that patients with CBMs were older, and had more severe Parkinson’s symptoms and cerebrovascular lesions.

No. 4 – “Vitamin B12 Supplements May Help Slow Parkinson’s Progression, Study Finds

Patients at early stages of Parkinson’s with low levels of vitamin B12 may experience faster motor and cognitive decline. Prior work had shown that B12 deficiencies can induce neurological and motor symptoms associated with Parkinson’s, including depression, paranoia, muscular numbness, and weakness. This study differed in that it was conducted in untreated patients earlier in the disease course, and found slower progression in those taking a multivitamin supplement. Overall, the findings suggest that vitamin supplements may help slow symptom progression.

No. 3  “Xadago, Cannabinoids, Opioids May Be Best to Manage Parkinson’s Pain, Review Suggest

Pain is a frequent non-motor symptom of Parkinson’s disease. A review study found that its management may be most effective with Xadago (safinamide, by US WorldMeds) or with cannabinoids and opioids.  Other approaches, such as multidisciplinary team care, Comtan (entacapone) and Tasmar (tolcapone) may also provide pain relief. In turn, the investigational treatment pardoprunox (SLV-308) and surgery reported only moderate benefits on reducing pain severity.

No. 2 – “Medical Cannabis Helps Older People with Parkinson’s, Other Diseases, Study Finds

Medical cannabis is a safe and effective option to ease pain in older patients with Parkinson’s, cancer, or other illnesses. In a study involving 2,736 people 65  years or older, its use over six months enabled a reduction or discontinuation of opioid pain medications in over 18% of patients. Participants also reported an improved quality of life. The most common adverse events were dizziness and dry mouth, reported by 7.1% of patients.

No. 1 – “Vitamin B3 Compound May Prevent Motor Decline in Parkinson’s Disease, Study Says

Out most widely read article of 2018 reported that a form of vitamin B3 — nicotinamide riboside — prevented the loss of motor function and lessened nerve cell death in a fly model of Parkinson’s. It also increased the levels of a metabolic compound called NAD+ and improved energy balance in fish neurons with a defective GBA gene — the most frequent gene risk for Parkinson’s — and defects in mitochondria, the cell’s powerhouse. The researchers suggested that this form of vitamin B3 may help treat impaired mitochondria function, which has been linked to Parkinson’s development.

 

At Parkinson’s News Today, we hope that these articles,  along our continuing reporting throughout 2019, help to educate, inform, and improve the lives of patients and their loved ones.

We wish all our readers a happy 2019.

 

The post Top 10 Parkinson’s Stories of 2018 appeared first on Parkinson’s News Today.

Inhibiting USP13 Enzyme Can Help Destroy Toxic Alpha-Synuclein Clumps, Mouse Study Finds

USP13 parkin alpha-synuclein

Inhibiting an enzyme called USP13 may represent an attractive therapeutic target for Parkinson’s and other neurodegenerative diseases, preclinical data suggests.

These findings also could hold important implications for a therapy currently being developed to treat Parkinson’s disease — nilotinib.

The study, “Ubiquitin specific protease-13 independently regulates parkin ubiquitination and alpha-synuclein clearance in alpha-synucleinopathies,” was published in Human Molecular Genetics.

USP13 belongs to a large family of enzymes called de-ubiquitinases known for their ability to cut chains of a small protein known as ubiquitin that is present inside stress-induced clumps of proteins and other molecules.

Ubiquitination is like a cellular tagging system: By adding an ubiquitin molecule to a protein, it marks it for degradation.

Previous research has shown that USP13 and another similar enzyme called USP5 are important in helping to dismantle clumps of molecules that form when cells are stressed by external factors, called “stress granules.”

Now Georgetown University Medical Center researchers have found that one reason clumps of alpha-synuclein, known as Lewy bodies, develop and accumulate in the brain is that USP13 removes all the “tags” placed on alpha-synuclein that mark it for destruction, or ubiquitination. Toxic aggregates of alpha-synuclein accumulate and are not efficiently cleared.

Researchers analyzed brain tissue samples collected postmortem from 11 patients with Parkinson’s disease. USP13 levels were about 3.5 times higher than samples from subjects not affected by Parkinson’s.

To better understand the role of USP13, researchers used a genetic approach to either increase or decrease the levels of USP13 in mouse neurons cultured in a laboratory dish. These neurons expressed high levels of alpha-synuclein.

The presence of alpha-synuclein alone significantly increased the levels of parkin ubiquitination. Parkin is a protein often found mutated in some Parkinson’s patients.

The team had previously shown that an increase in parkin ubiquitination led to clearance of neurotoxic proteins, including alpha-synuclein, in several animal models of neurodegeneration.

However, expression of high levels of USP13 and alpha-synuclein together significantly reduced parkin ubiquitination, suggesting that USP13 can modulate parkin response.

“Taken together, these data suggest that USP13 may regulate parkin ubiquitination/de-ubiquination cycle,” the researchers wrote.

Additional experiments revealed that decreasing the levels of USP13 increased alpha-synuclein ubiquitination and destruction.

Knocking out the USP13 gene in a mouse model of Parkinson’s disease was able to prevent alpha-synuclein-induced death of dopamine-producing brain cells. Also, genetic inhibition of USP13 led to significant improvement in animals’ motor performance, while improving the clearance of alpa-synuclein toxic molecules.

Importantly, researchers found that a new therapy being studied to treat Parkinson’s disease, nilotinib, worked better when USP13 was inhibited.

Results from a recent Phase 2 clinical trial (NCT02954978) conducted by Novartis showed that nilotinib can modulate dopamine levels and metabolism, as well as prevent the formation of toxic alpha-synuclein aggregates.

Nilotinib is available under the brand name Tasigna as an approved treatment for certain types of leukemia.

“Our discovery clearly indicates that inhibition of USP13 is a strategic step to activate parkin … to increase toxic protein clearance,” Charbel Moussa, PhD, director of Georgetown University Medical Center Translational Neurotherapeutics Program and senior author of the study, said in a press release. “Our next step is to develop a small molecule inhibitor of USP13 to be used in combination with nilotinib in order to maximize protein clearance in Parkinson’s and other neurodegenerative diseases.”

The post Inhibiting USP13 Enzyme Can Help Destroy Toxic Alpha-Synuclein Clumps, Mouse Study Finds appeared first on Parkinson’s News Today.

Phase 2 Trial Shows Nilotinib Potential to Modulate Dopamine in Parkinson’s

Nilotinib Phase 2 trial

Nilotinib can modulate dopamine levels and metabolism, as well as prevent the formation of toxic alpha-synuclein aggregates, according to recent data from a Phase 2 clinical trial.

These findings suggest that Novartis’ investigational therapy has the potential to promote long-term benefits in patients with Parkinson’s disease.

The study, “Nilotinib increases dopamine metabolism and reduces oligomeric: total alpha-synuclein ratio in Parkinson’s disease,” was recently presented during the 2018 World Congress on Parkinson’s Disease and Related Disorders (IAPRD), Lyon, France.

Nilotinib is available under the brand name Tasigna as an approved treatment for certain types of leukemia. It blocks the activity of a protein called BCR-ABL that is known to support cancer development. But this protein also is intimately linked to several mechanisms in the brain, such as oxidative stress and alpha-synuclein-induced neurodegeneration, which play critical roles in Parkinson’s and other brain disorders.

Results of a small proof-of-concept Phase 1 trial (NCT02281474) performed at Georgetown University in Washington, D.C., revealed that treatment with two different doses of Nilotinib — 150 mg and 300 mg — could improve Parkinson’s patients’ motor skills and cognitive abilities. In addition, the treatment showed the potential to reduce levels of the protein alpha-synuclein, which is believed to contribute to destruction of brain nerve cells in Parkinson’s disease.

In the ongoing Phase 2 trial (NCT02954978) a total of 75 patients with mid-stage Parkinson’s disease with mild cognitive impairment were randomized to take one of four tested oral doses of Nilotinib -—150 mg, 200 mg, 300 mg, and 400 mg — or a placebo.

After a single treatment researchers evaluated several biomarkers of the disease, including the levels of alpha-synuclein and dopamine derivate compounds in patients’ cerebrospinal fluid (CSF).

The data revealed a significant increase in homovanillic acid (HVA) and DOPAC levels, suggestive of enhanced production and metabolism of dopamine just one to four hours after treatment.

Although researchers could not find significant changes in CSF total alpha-synuclein levels, low-dose Nilotinib therapy (150 mg and 200 mg) resulted in a reduction of the levels of abnormally clustered and toxic alpha-synuclein.

“The significant reduction of oligomeric alpha-synuclein, which is expected to increase in the CSF of Parkinson’s disease patients as the disease progresses, suggests that Nilotinib may reduce misfolded alpha-synuclein accumulation and have a long-term disease modifying effect,” researchers wrote.

“These results suggest Nilotinib, in a dose dependent manner, may have a symptomatic effect through modulation of brain dopamine levels. Additionally, the significant reduction of oligomeric alpha-synuclein, which is expected to increase in the CSF of PD patients as the disease progresses, suggests that Nilotinib may reduce misfolded alpha-synuclein accumulation and have a long-term disease modifying effect,” researchers wrote.

The team will continue the analysis of the collected data to further explore the impact of Nilotinib treatment on disease biomarkers’ levels both in the blood and CSF, after a single administration and 52-week daily treatment regimen.

A new Phase 2 trial, NILO-PD (NCT03205488), currently recruiting 135 participants, will further investigate the potential of Nilotinib in patients with moderate-to-advanced Parkinson’s symptoms.

The study will take place at 25 sites across the United States. It will compare the safety and effects on patients’ motor functions of once-daily Nilotinib versus placebo treatment, for up to 12 months.

The post Phase 2 Trial Shows Nilotinib Potential to Modulate Dopamine in Parkinson’s appeared first on Parkinson’s News Today.

Source: Parkinson's News Today

Phase 2 Trial Testing Leukemia Treatment, Nilotinib, in Range of Parkinson’s Patients

clinical trial recruiting

People with Parkinson’s disease are being recruited for a new clinical trial testing nilotinib, an FDA-approved leukemia treatment, in a range of patients.

The two-part Phase 2 trial (NCT03205488), called NILO-PD, is a randomized, double-blind, and placebo-controlled study taking place at 25 sites across the U.S. Part one will evaluate the safety and tolerability of different dosing levels of oral nilotinib (150 mg or 300 mg given daily) or placebo in about 75 people with moderate to advanced Parkinson’s symptoms for 8.5 months.

Depending on results, another 60 patients with early disease symptoms will be recruited into part two. Patients will receive either the optimal dose determined from the trial’s first phase or placebo, and be regularly evaluated for 14.5 months.

Treatment tolerability and safety at six and 12 months are the trial’s main goals, but patients will also be assessed for the treatment’s potential to slow disease progression.

Nilotinib, available as a treatment for chronic myelogenous leukemia under the brand name  Tasigna, is a tyrosine kinase inhibitor that works by blocking a protein called BCR-ABL, whose activity is uncontrolled in cancer cells and leads to cell proliferation. Previous studies have shown that this protein can accumulate in the brain and is linked to several pathways — such as oxidative stress and  alpha-synuclein-induced neurodegeneration — relevant in Parkinson’s disease.

Results of a small proof-of-concept Phase 1 trial (NCT02281474), performed at Georgetown University, found two different doses of nilotinib — 150 mg and 300 mg – were well-tolerated by advanced Parkinson’s patients. Importantly, the results also suggested that the therapy may improve patients’ motor skills and cognitive abilities.

The study “Nilotinib Effects in Parkinson’s disease and Dementia with Lewy bodies” was published in the IO Press Journal in 2016.

The new trial, supported by a Michael J. Fox Foundation research grant, aims to further investigate those findings. It is led by Tanya Simuni, director of the Parkinson’s Disease and Movement Disorders Program at Northwestern University, working with the nonprofit Parkinson’s Study Group.

Specifically, researchers want to determine nilotinib’s long-term safety and effectiveness in easing symptoms. Efficacy will be assessed after six months using the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) motor score.

Enrollment information for this study, which runs through October 2020, is available by clicking here.

This study is an example of the potential of repurposing FDA-approved drugs for other diseases other than original. This can lead to faster approved therapies, since repurposed therapies have already been tested for safety and tolerability in Phase 1 trials with human volunteers.

However, the therapy’s efficacy in a new disease setting needs to be evaluated in well controlled Phase 2 and 3 clinical trials.

Researchers at the University of Rochester Medical Center’s Clinical Trials Coordination Center (CTCC) are also helping to lead the Phase 2 study.

The post Phase 2 Trial Testing Leukemia Treatment, Nilotinib, in Range of Parkinson’s Patients appeared first on Parkinson’s News Today.

Source: Parkinson's News Today