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LRRK2 Inhibitors May Benefit Parkinson’s Patients With and Without Genetic Mutation, Study Finds

LRRK2

Inhibiting the activity of LRRK2 kinase — an enzyme whose mutated form is one of the most common genetic causes of Parkinson’s disease — may benefit patients both with and without this disease-related mutation, a study finds.

Molecules that block the activity of the LRRK2 kinase — such as DNL201 and DNL151, both being developed by Denali Therapeutics — are currently being tested in clinical trials.

The results of this study, “LRRK2 inhibition prevents endolysosomal deficits seen in human Parkinson’s disease,” were published in Neurobiology of Disease. The research was supported by the Michael J. Fox Foundation.

Mutations in the leucine rich repeat kinase 2 (LRRK2) gene are one of the most commonly known genetic causes of Parkinson’s disease. Evidence indicates that in people with idiopathic Parkinson’s, in which the disease has no known cause, the LRRK2 protein is overly active, regardless of the patient’s mutation status — whether or not they have a mutated LRRK2. That overly active protein leads to the malfunctioning of lysosomes, the special compartments within cells that digest and recycle different types of molecules. Lysosomal dysfunction is involved in the formation of  protein aggregates, or clumps, called Lewy bodies, which contribute to Parkinson’s and, therefore, neurodegeneration.

Therapies that can inhibit, or block LRRK2 are currently being tested in human clinical trials. However, it is still unclear whether blocking LRRK2 protein activity in people with idiopathic Parkinson’s can prevent lysosomal dysfunction and consequent neurodegenerative processes.

To learn more, investigators at the University of Pittsburgh now studied post-mortem brain samples, specifically from a motor brain region called the substantia nigra, which is severely damaged in Parkinson’s. The researchers characterized lysosomal abnormalities in the surviving dopaminergic neurons — the main source of dopamine, the loss of which is a hallmark of this disease — of idiopathic Parkinson’s patients.

When compared with healthy controls, Parkinson’s patients had more abnormal lysosomes. These changes occurred during the early stages of lysosomal development, the researchers found.

The team then investigated whether these post-mortem cellular findings could be replicated in an animal model of Parkinson’s. Rats were given two distinct dose regimens of rotenone, a pesticide that inhibits mitochondria, or the “powerhouses” of cells. Blocking mitochondria leads to cellular death and the onset of parkinsonian features.

Nine to 14 daily doses of rotenone reproduced many idiopathic Parkinson’s features, including lysosomal defects. This caused neurodegeneration in the striatum and substantia nigra, two brain areas involved in motor control.

Interestingly, five daily doses of the pesticide weren’t enough to cause cell death, but did increase the accumulation of Parkinson’s-related alpha-synuclein protein and produce changes in lysosomes.

“These data demonstrate that, in rotenone-treated rats, [alpha]-synuclein protein levels rise in the dopaminergic neurons prior to the onset of frank neurodegeneration,” the researchers said.

When overactive LRRK2 was blocked in rotenone-treated rats, the protein’s activity was reduced. That, in turn, improved the overall health of lysosomes and prevented the accumulation of alpha-synuclein. These effects were observed in animals without a genetic predisposition to develop Parkinson’s, suggesting that the LRRK2 kinase inhibitors may be effective beyond LRRK2-mutated patients.

“Our work suggests that drugs that block LRRK2, some of which have entered clinical trials, will be useful for people with typical Parkinson’s disease,” J. Timothy Greenamyre, MD, PhD, the study’s lead author, said in a press release.

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First Parkinson’s Patient Dosed in Early Trial of DNL151, Potential LRRK2 Inhibitor

DNL151 early trial

A Phase 1b clinical trial exploring the oral LRRK2 inhibitor DNL151 has started dosing Parkinson’s patients, the therapy’s developer Denali Therapeutics announced.

The 28-day, multicenter, and double-blind study (NCT04056689) is testing two doses of DNL151 against placebo in people with mild to moderate Parkinson’s disease, and with or without LRRK2 mutations, the most common genetic cause of the disease.

Twenty-four patients, ages 30 to 75, are expected to take part in the trial, and enrollment is ongoing at the Centre for Human Drug Research, in Leiden, the Netherlands. More information and contacts can be found here.

The company also announced the launch of its Engage Parkinsons website, where patients, caregivers, healthcare professionals, and advocates can find information about the disease and its link with genetics, overall advancements in Parkinson’s research, and Denali’s clinical trials. Registrants will also be informed about future studies sponsored by Denali.

“We are encouraged by the progress with our LRRK2 clinical program,” Ryan Watts, PhD, Denali’s CEO, said in a press release. “The launch of our Engage Parkinson’s website is intended to strengthen our engagement and interactions with the Parkinson’s disease patient community.”

“This is an important part of our efforts to connect with patients who may be eligible for our current and future clinical trials.”

DNL151 is a small molecule inhibitor of LRRK2, a protein that regulates the activity of cellular structures called lysosomes — tiny vesicle were a cell’s waste is broken down and recycled. High levels of LRRK2 impair lysosomal function, and may result in the formation of toxic protein clumps called Lewy bodies in brain cells. Lewy bodies are associated with neurodegeneration.

By selectively suppressing LRRK2, DNL151 aims to restore lysosomal function, which, according to Denali, may slow Parkinson’s progression in all patients.

The Phase 1b trial will primarily assess the safety, tolerability, pharmacokinetics — a compound’s absorption, distribution, metabolism, and excretion — and overall impact on the body of a high and low dose of DNL151. Biomarkers of target binding and exploratory clinical endpoints (goals) will also be evaluated.

Participants will be randomly assigned to either dose of DNL151, or a placebo. Study completion is expected by February 2020.

“Based on data generated from our prior study in healthy volunteer subjects, we are excited to evaluate DNL151 in Parkinson’s disease patients,” said Carole Ho, MD, Denali’s chief medical officer. “We believe that this study will provide additional important safety and biomarker data in patients to inform the choice between either DNL151 or DNL201 for potential registrational trials.”

These future trials are expected to form the basis of requests for regulatory approval of either therapy.

DNL201 is the company’s lead candidate for Parkinson’s disease, and is also an oral LRRK2 inhibitor able to reach the brain. A Phase 1 trial (NCT03710707) has a similar design to DNL151’s Phase 1 study, but is taking place at sites across the U.S. It is expected to conclude shortly.

Preclinical work supports the potential therapy’s ability to substantially inhibit LRKK2 activity even when administrated at lower dose.

Reported results of a prior Phase 1 study showed that DNL201 was safe and well-tolerated in healthy volunteers, and it demonstrated an ability to effectively suppress LRRK2 effects, as measured by blood biomarkers.

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CENTOGENE, Denali Partnering to Recruit LRRK2 Parkinson’s Patients for Clinical Trials

CENTOGENE, Denali collaboration

CENTOGENE and Denali Therapeutics are teaming up to identify and recruit Parkinson’s disease patients who carry mutations in the LRRK2 gene for future clinical trials, the companies announced.

CENTOGENE will carry out a targeted global recruitment campaign to identify and characterize Parkinson’s patients with LRRK2 mutations  and sequence the LRRK2 gene in this population, using its proprietary CentoCard, a dried blood spot collection kit.

CENTOGENE-recruited patients will participate in clinical trials supporting Denali’s LRRK2 inhibitor therapy program.

Mutations in the LRRK2 gene are one of the most commonly known genetic causes of Parkinson’s disease and usually result in the malfunctioning of lysosomes — special compartments within cells that digest and recycle different types of molecules.

Lysosomal dysfunction is involved in the formation of Lewy body protein aggregates and, therefore, neurodegeneration. LRKK2 regulates the formation and function of lysosomes, which are impaired in Parkinson’s disease and may eventually be restored by inhibiting LRRK2 activity, both in patients with a genetic LRRK2 mutation as well as in those with sporadic Parkinson’s disease.

“Our exclusive collaboration underscores CENTOGENE’s CEO and founder of CENTOGENE, said in a press release. “We believe we can contribute to Denali’s development of disease modifying medicines for patients with Parkinson’s disease. CENTOGENE will help Denali speed up the enrollment of patients in clinical studies for its LRRK2 program.”

CENTOGENE’s dried blood spot collection kit contains a validated procedure to extract high-quality DNA, enzymes, and biomarkers from patients’ blood samples. The technology has several advantages, including ease of handling — the samples are stable once they are dry and can be sent to CENTOGENE by regular mail — no sensitivity over time or to temperature, and cost-effectiveness.

This aids in the delivery of biological samples and makes genetic, enzymatic, and biomarker testing available worldwide.

After the identification of LRRK2 Parkinson’s patients, data will be sent to Denali to potentially recruit patients for its clinical trials testing LRRK2 inhibitor therapies.

Denali’s Parkinson’s pipeline includes two investigational LRRK2 inhibitors currently in the early phase of development, DNL201 and DNL151.

The company’s latest results revealed that DNL201 was safe and well-tolerated by healthy individuals in a Phase 1 clinical trial. The investigational therapy is currently being tested in a dose-escalation Phase 1 study in healthy volunteers in the Netherlands.

“Denali is the first company to conduct clinical trials with LRRK2 inhibitors for the treatment of Parkinson’s disease. This partnership with CENTOGENE is a central part of our global efforts to identify and recruit PD [Parkinson’s disease] patients with a mutation in the LRRK2 gene into our planned clinical studies,” said Carole Ho, MD, chief medical officer and head of development at Denali. “We are impressed with CENTOGENE’s approach and technology and believe that our joint efforts will accelerate the enrollment of PD patients and the completion of our clinical trials.”

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