Implementing a National Biobank of PD With WGS and Functional Assessment of Polygenic Inheritance by iPSC Technology

Implementing a National Biobank of Genetic, Sporadic and Prodromic Parkinson's Disease With Whole Genome Analysis and Functional Assessment of Polygenic Inheritance by iPSC Technology

The genetic complexity and heterogeneity of the sporadic forms of Parkinson's disease (PD) are posing a formidable challenge to disentangle their direct molecular causes. To advance this research, we plan to coordinate our local biorepositories of PD biological specimens creating a standardized and integrated national resource. In this framework, we plan to collect more samples from additional sporadic PD cases and to extend the sampling to patients with REM sleep behavior disease. We plan a large campaign of whole genome sequencing including about 200 patients to identify rare genomic variants plausibly associated with these diseases. In addition, we will standardize the generation and quality control of iPSC lines to make available to the scientific community. Finally, we will combine iPSC technology and gene editing to functionally assess the relative impact of rare variants in coding regions inherited together as a polygenic trait previously identified in selected sporadic PD cases

Study Overview

• Status: Recruiting
• Conditions: Parkinson Disease; REM Sleep Behavior Disorder
• Intervention / Treatment: Genetic: whole genome sequencing

Detailed Description

The project is a multicentric observational study. Instuitutions involved are:

IRCCS Hospital San Raffaele, Milan Italy (coordinator Operating Unit (OU1)) IRCCS INM Neuromed, Pozzilli, (IS) Italy (Operating Unit (OU2)) IRCCS San Raffaele Roma, (Operating Unit (OU3)) The project takes advantage from the availability of a large collection of PD samples (~800) PD from familiar and sporadic cases, recruited at IRCCS Neuromed, for which we already collected and stored clinical information, genetic data as well as DNA, serum, plasma and peripheral blood mononuclear cells (PBMCs) for the entire study cohort.

The activities of the IRCCS INM Neuromed are:

1. standardization of the clinical reporting, sample collection, storage and identification between the centers;
2. recruitment of 100 PD patients, 30 RBD patients and 100 healthy subjects (patients' wives/husbands), to be carried out during the scheduled outpatient visits for these patients;
3. whole genome sequencing (WGS) and bioinformatic analysis (in collaboration with OU1) of a selected cohort of PD patients (200 samples), negative for mutations/variants in PD candidate genes;
4. WGS analysis of REM sleep behaviour disorder (RBD) prodromal patients as a model to identify early biomarker for PD;
5. development of an innovative protocol for early diagnosis of PD based on the co-inheritance of multiple rare deleterious variants in PD genes;
6. generation of induced pluripotent cell lines (iPSC) by reprogramming PBMCs from PD patients and familiar healthy donors.

After signed informed consent patients will be assessed for disease progression (Stadio di Hoehn and Yahr, MDS-UPDRS part III, MOCA test, no motor symptoms, therapy and LID occurrence, sleep behavior disease). Each patient and control will be subjected to peripheral blood sampling for the isolation of DNA, plasma, serum, PBMC. For a subset of patients induced pluripotent stem cells (iPSC) will be generated starting from PBMC.

Whole genome sequencing approach will be used to identify novel associated vatiants.

Extensive computational analysis will be planned to map the SNPs to regulatory regions controlling the expression of selected genes. This effort will provide the initial knowledge to draft the association between particular genomic SNPs and their combinations with sporadic PD. This endeavor is critical to advance our understanding of the genetic roots of PD and is in line with analogous ongoing international studies with whom will seek coordination. The success of this research will provide the means for developing predictive genetic testing and counselling of patients with PD and their families.

To increase the power analysis data will be analyzed including WES data of a cohort of 800 PD patients and 300 healthy subject already available at IRCCS INM Neuromed.

• Study Type: Observational
• Enrollment (Estimated): 230

Contacts and Locations

• Study Contact: Name: Vania Broccoli, PhD; Phone Number: +39 0226434616; Email: broccoli.vania@hsr.it

Study Locations

• Italy
  • Italy
    • Milan, Italy, Italy, 20132
      • Recruiting
      • IRCCS San Raffaele
      • Contact: Vania Broccoli, PhD; Phone Number: 0226434616; Email: broccoli.vania@hsr.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

The study includes 100 PD patients, 30 RBD and 100 age/gender-matched controls. All PD patients will be diagnosed at the IRCCS Neuromed and followed-up (at least for 3 years) for disease progression

Description

Inclusion Criteria PD patients:

• Presence of at least 2 of the 4 cardinal signs (tremor, rigidity, bradykinesia, onset asymmetric) one of which must be tremor or bradykinesia;
• Absence of atypical symptoms such as: i) early postural instability, freezing phenomena, cognitive impairment, hallucinations, pathological involuntary movements, vertical gaze paralysis; ii) confirmed causes of secondary parkinsonism (focal lesions, drugs, substances toxic);
• Documented response to L-dopa or dopamine agonist use (or lack of adequate therapeutic attempt with L-dopa or dopamine agonists).

Inclusion Criteria RBD patients:

• Subjects affected by idiopathic RBD that will be selected according to the most recent criteria international classification of sleep disorders (ICSD-3).

Exclusion Criteria:

• pre-existing psychiatric conditions;
• Neurodegenerative neurological diseases such as multiple sclerosis, lateral sclerosis amyotrophic, Alzheimer's, neuromuscular pathologies, epilepsy;
• diagnosis of dementia;
• depression;
• prolonged intake of anxiolytics, antidepressants, antipsychotics, hypnotic drugs, cognitive stimulants

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
motor and non motor symptoms of PD and RBD patients will be evaluated with MDS-UPDRS	The MDS-UPDRS has four parts, namely, I: Non-motor Experiences of Daily Living; II: Motor Experiences of Daily Living; III: Motor Examination; IV: Motor Complications. Twenty questions are completed by the patient/caregiver	2 years
clinical evaluation of of sleep disorders in PD and RBD patients	presence of sleep disorders will be evaluated by Munich Parasomnia Screening (MUPS)	2 years
clinical evaluation of of sleep disorders in PD and RBD patients by Polysomnography	Sleep microstructure will be evaluated by analysis of the alternating cyclic pattern (CAP), a marker of NREM sleep instability.	2 years
clinical evaluation of cognitive impairment of PD and RBD patients by MoCA test score	The Montreal Cognitive Assessment (MoCA) is a test used by healthcare providers to evaluate people with memory loss or other symptoms of cognitive decline. The MoCA contains 30 questions and checks different types of cognitive or thinking abilities. These include:orientation, short-term memory/delayed recall, executive function/visuospatial ability, clock-drawing test.	2 years
clinical evaluation of levodopa-induced dyskinesia (LID) in PD patients	LID occurrence will be related to levodopa dosage and time of therapy	2 years
association with phenotypic manifestation of PD	The presence of one or more variants will be tested for association with phenotypic manifestation of PD (motor, non motor, and cognitive signs, as well as age at onset, LID and neuroimaging changes) to assess the variant burden effect on progression, and prognosis of the disease	2 years
motor symptoms of PD and RBD patients will be evaluated with Hoehn and Yahr (HY) score	The Hoehn and Yahr Scale will be used to measure how Parkinson's symptoms progress and the level of disability. It includes stages 1 through 5: Stage 1. Unilateral involvement only, usually with minimal or no functional impairment; Stage 2 = Bilateral disease, without impairment of balance; Stage 3 = Mild to moderate bilateral disease; some postural instability; physically independent. Stage 4 = Severe disability; still able to walk or stand unassisted. Stage 5 = Wheelchair bound or bedridden unless aided.	2 years
identification of variants/mutations	the number of multiple rare (Minor allele frequency, MAF<0.01) deleterious (missense, non sense, frameshift and splicing) variants in PD genes will be counted in PD patients and unrelated healthy subjects. Case-control assoiciation study will evaluate the PD risk	2 years

Collaborators and Investigators

• Sponsor: IRCCS San Raffaele
• Investigators: Principal Investigator: Vania Broccoli, PhD, IRCCS San Raffaele

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2023
• Primary Completion (Actual): March 4, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: January 30, 2023
• First Submitted That Met QC Criteria: February 8, 2023
• First Posted (Actual): February 10, 2023

Study Record Updates

• Last Update Posted (Actual): March 30, 2026
• Last Update Submitted That Met QC Criteria: March 25, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Synucleinopathies; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurodegenerative Diseases; Sleep Wake Disorders; Movement Disorders; Parkinsonian Disorders; Basal Ganglia Diseases; Parasomnias; REM Sleep Parasomnias; Parkinson Disease; REM Sleep Behavior Disorder; Investigative Techniques; Genetic Techniques; Sequence Analysis; Sequence Analysis, DNA; Whole Genome Sequencing
• Other Study ID Numbers: PNRR-MAD-2022-12375960

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: genetic data

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No