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Centogene Launches 2-Year Global ROPAD Study to Assess the Genetics of Parkinson’s Disease

ROPAD study, Parkinson's genetics

A two-year, global, observational study that will assess the contribution of genetic factors in the development of Parkinson’s disease has been launched by Centogene, in collaboration with the University of Lübeck.

The new study (NCT03866603), which is called “Rostock International Parkinson’s Disease Study” or ROPAD, seeks to enroll around 10,000 participants worldwide to get a representative snapshot of the genetic variability in a large population of patients with this progressive neurodegenerative disease.

Adult individuals, 18 or older, who have been clinically diagnosed with Parkinson’s disease are eligible to participate in the study, as well as individuals who are family members of a patient with LRRK2 parkinsonism or are at high risk of having the disease.

The main goal of the study is to pinpoint the specific genetic mutations and genes that may be associated with the development of Parkinson’s disease.

The study’s primary outcome will be to assess the number of patients carrying mutations in the LRRK2 gene, in which more than 100 different mutations associated with late-onset Parkinson’s disease have already been identified. The researchers will also assess, as the study’s secondary outcomes, the prevalence of mutations in other genes previously linked to Parkinson’s, such as GBA.

All the genetic analysis will be performed using the CentoCard, Centogene’s proprietary, CE-marked device that has been designed to collect and evaluate dried blood spot samples.

“Centogene is committed to bringing hope to patients and their families by shortening the diagnostic odyssey, and we are proud to be working on this important study that may have vast implications for the future diagnosis and treatment of Parkinson’s disease,” Arndt Rolfs, CEO and founder of Centogene, said in a press release.

“All too often clinical studies do not reflect the ethnic diversity of the world, and this study is unique in that we are working across all ethnicities worldwide and crosschecking the effect of environmental components and individual genetics. We are excited about the contribution that Centogene and our partners are making in discovering deeper insights into Parkinson’s disease genetics,” Rolfs added.

Patients carrying genetic mutations linked to the development of Parkinson’s disease will have the opportunity to participate in the “LRRK2 International Parkinson’s Disease Project (LIPAD),” a study led by professor Christine Klein at the University of Lübeck which is designed to document the frequency of all signs and symptoms of Parkinson’s disease among this particular population.

In addition, patients participating in ROPAD who are carriers of LRRK2 mutations will have the chance to enroll in future clinical studies led by Denali Therapeutics, Centogene’s study partner, which is currently working on a set of new investigational therapies for neurodegenerative disorders.

To know more about the ROPAD trial and how to participate, visit Centogen’s webpage or its ClinicalTrial.gov registry page.

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Sirion and Denali Collaborating to Develop Gene Therapies for Neurodegenerative Diseases

gene therapies, Denali, Sirion

Sirion Biotech and Denali Therapeutics have agreed to partner on the development of gene therapies for Parkinson’s disease and other neurodegenerative disorders.

According to the license and collaboration agreement, the two companies will pursue the development of harmless, next-generation adeno-associated viral vectors (AAV) able to cross the blood-brain barrier — a semipermeable membrane that protects the brain against the external environment.

Besides Parkinson’s, these potential gene therapies will also target Alzheimer’s, amyotrophic lateral sclerosis, and other diseases of the central nervous system — brain and spinal cord.

“This ground-breaking collaboration will help Denali Therapeutics to increase the availability of protein therapeutics in the brain, and to quickly enter clinical trials with efficient, safe and scalable therapeutic candidates,” Christian Thirion, PhD, Sirion’s founder and CEO, said in a press release.

According to Sabine Ott, PhD, Sirion’s vice president of business development and licensing, the company believes that through its partnership with Denali, AAV-based gene therapies can reach the market “in the fastest possible way, providing novel treatment options to many millions of patients.”

Specifically, the aim is to create new and modified AAV capsids (the protein shell of a virus) that are safe and have greater specificity and high efficiency to deliver therapeutic levels of medicines to the brain. AAV vectors are regarded as the most promising gene delivery system for therapies.

Sirion’s collaboration with Dirk Grimm, PhD, a professor of viral vector technologies at Heidelberg University Hospital in Germany, will play a key part in the research.

“By contributing and harnessing our unique and proprietary expertise in the engineering and high-throughput in vivo screening of AAV capsid libraries, we will significantly accelerate this joint endeavour and increase our chances to realize its pivotal aims,” Grimm said.

The main terms of the agreement between Germany-based Sirion and San Francisco-based Denali include development expenses, milestone payments to Sirion, and royalties from future products or therapies.

According to Alexander Schuth, Denali’s chief operating officer, the company is “excited to partner with Sirion” and combine its “expertise around the blood-brain barrier and neurodegenerative diseases with Sirion’s leading expertise on viral vectors for gene therapy to enable new treatments for diseases of the brain,” further saying that the partnership will add a new therapeutic modality to the company’s portfolio and is complementary to other programs from Denali.

In October 2018, Denali and Centogene announced a collaboration to identify and recruit Parkinson’s patients carrying mutations in the LRRK2 gene for future clinical trials. Mutations in LRRK2 are a well-known genetic cause of Parkinson’s. These patients will participate in trials of Denali’s LRRK2 inhibitor therapy program, which includes DNL201 and DNL151.

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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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Potential Parkinson’s Treatment, DNS201, Safe and Well-Tolerated in Phase 1 Study, Denali Says

DNL201 Phase 1 results

Denali Therapeutics’ reports that its investigational compound for Parkinson’s disease, DNL201, was found to be safe and well-tolerated by healthy individuals in a Phase 1 clinical trial. The company is planning to advance the compound into a Phase 1b study in patients, a press release states.

DNL201 is an inhibitor of leucine-rich repeat kinase 2 (LRRK2). Mutations in the LRRK2 gene are the most frequent genetic cause of Parkinson’s and are usually associated with problems in the working of lysosomes, a structure within cells that breaks down molecules and provides the cell with the simpler nutrients it requires.

Lysosomal dysfunction contributes to the formation of Lewy body protein aggregates, and consequently, neurodegeneration. LRRK2 is known to regulate 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.

The randomized, double-blind, placebo-controlled Phase 1 study investigated the safety, pharmacokinetic and pharmacodynamic of  DNL201 in more than 100 healthy individuals. Pharmacokinetics refers to a drug’s absorption, bioavailability, distribution, metabolism, and excretion in the body; pharmacodynamics refers to the relationship between a medicine’s concentration at the site of action and the resulting effect, including the time course and intensity of therapeutic and adverse effects.

Participants took single or multiple ascending doses of DNL201 or placebo, the company reports, adding that all were generally well-tolerated, with no serious side effects.

Treatment was also well-tolerated at elevated doses that achieved high levels of cerebrospinal fluid (CSF) exposure. LRRK2 inhibition was effective, as measured by two blood biomarkers and effects on lysosomal function — the main mechanism affected by LRRK2 mutations.

“We conclude from this clinical trial that DNL201 was able to achieve the targeted levels of LKKR inhibition at doses that were safe and well-tolerated,” Carole Ho, MD and chief medical officer of Denali Therapeutics, said in the release.

“We are pleased that the trial was a success in all these key measures. The trial data give us confidence to proceed with further clinical testing in Parkinson’s patients and provide a solid basis for selection of the optimal dose for future clinical trials in patients,” Ho added.

Preclinical studies demonstrated DNL201’s capacity to stop an average 90 percent of LRKK2 activity at its highest concentration and 50 percent when the compound’s levels dropped to a lower concentration, showing its potential as a Parkinson’s therapy. The release did not specify what dose levels were used, and a trial document was not available on clinicaltrials.gov website.

Details of the Phase 1 study will be presented at a future medical conference, Denali said.

“We are leading the way in testing LRRK2 inhibitors in humans with the goal of bringing a disease modifying therapeutic to patients suffering from Parkinson’s disease,” said Ryan Watts, PhD and chief executive officer of Denali. “We are also encouraged to see mounting evidence supporting a role of LRRK2 inhibition in the broader sporadic Parkinson’s disease population, in addition to Parkinson’s disease genetically associated with a LRRK2 mutation.”

Denali is developing a second inhibitor of LRRK2, called DNL151, that is now testing in a dose-escalation Phase 1 study in healthy volunteers in the Netherlands.

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Source: Parkinson's News Today