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

• ClinicalTrials.gov Identifier: NCT05721911
• Recruitment Status: Not yet recruiting
• First Posted: February 10, 2023
• Last Update Posted: February 15, 2023
• Sponsor: Neuromed IRCCS
• Information provided by (Responsible Party): Teresa Esposito, Neuromed IRCCS

Tracking Information

• First Submitted Date: January 30, 2023
• First Posted Date: February 10, 2023
• Last Update Posted Date: February 15, 2023
• Estimated Study Start Date: June 2023
• Estimated Primary Completion Date: May 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 13, 2023)

• motor symptoms of PD and RBD patients will be evaluated with Hoehn and Yahr (HY) score [ Time Frame: 2 years ]
  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.
• motor and non motor symptoms of PD and RBD patients will be evaluated with MDS-UPDRS [ Time Frame: 2 years ]
  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
• clinical evaluation of of sleep disorders in PD and RBD patients [ Time Frame: 2 years ]
  presence of sleep disorders will be evaluated by Munich Parasomnia Screening (MUPS)
• clinical evaluation of of sleep disorders in PD and RBD patients by Polysomnography [ Time Frame: 2 years ]
  Sleep microstructure will be evaluated by analysis of the alternating cyclic pattern (CAP), a marker of NREM sleep instability.
• clinical evaluation of cognitive impairment of PD and RBD patients by MoCA test score [ Time Frame: 2 years ]
  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.
• clinical evaluation of levodopa-induced dyskinesia (LID) in PD patients [ Time Frame: 2 years ]
  LID occurrence will be related to levodopa dosage and time of therapy
• identification of variants/mutations [ Time Frame: 2 years ]
  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
• association with phenotypic manifestation of PD [ Time Frame: 2 years ]
  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

Original Primary Outcome Measures (submitted: February 8, 2023)

• motor symptoms of PD and RBD patients will be evaluated with Hoehn and Yahr score [ Time Frame: 2 years ]
  The Hoehn and Yahr Scale will be used to measure how Parkinson's symptoms progress and the level of disability
• motor and non motor symptoms of PD and RBD patients will be evaluated with MDS-UPDRS [ Time Frame: 2 years ]
  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
• clinical evaluation of of sleep disorders in PD and RBD patients [ Time Frame: 2 years ]
  presence of sleep disorders will be evaluated by Munich Parasomnia Screening (MUPS)
• clinical evaluation of of sleep disorders in PD and RBD patients by Polysomnography [ Time Frame: 2 years ]
  Sleep microstructure will be evaluated by analysis of the alternating cyclic pattern (CAP), a marker of NREM sleep instability.
• clinical evaluation of cognitive impairment of PD and RBD patients by MoCA test score [ Time Frame: 2 years ]
  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.
• clinical evaluation of levodopa-induced dyskinesia (LID) in PD patients [ Time Frame: 2 years ]
  LID occurrence will be related to levodopa dosage and time of therapy
• identification of variants/mutations [ Time Frame: 2 years ]
  assessing if the inheritance of multiple rare deleterious variants in PD genes is predictive of PD risk
• association with phenotypic manifestation of PD [ Time Frame: 2 years ]
  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

• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Implementing a National Biobank of PD With WGS and Functional Assessment of Polygenic Inheritance by iPSC Technology
• Official Title: 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
• Brief Summary: 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

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
• Study Design: Observational Model: Case-Control; Time Perspective: Prospective
• Target Follow-Up Duration: Not Provided

Biospecimen

Retention:   Samples With DNA

Description:

Blood samples for purification of DNA, plasma and serum and PBMC. hiPSC will be generated by reprogramming of PBMC.

• 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

Condition

• Parkinson Disease
• REM Sleep Behavior Disorder

Intervention

Genetic: whole genome sequencing

Partecipants 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 disorders. Partecipants will be subjected to peripheral blood sampling for the purification of DNA, plasma, serum, PBMC and generation of hiPSC. DNA of each partecipants we will analysed by whole genome sequencing by next generation sequencing to identify any variant in candidate PD genes

• Study Groups/Cohorts: Not Provided
• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Not yet recruiting
• Estimated Enrollment (submitted: February 8, 2023): 230
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: May 2025
• Estimated Primary Completion Date: May 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Teresa Esposito, PhD; +39 0865915249; teresa.esposito@igb.cnr.it

• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT05721911
• Other Study ID Numbers: PNRR-MAD-2022-12375960
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided
• Plan Description: genetic data

• Current Responsible Party: Teresa Esposito, Neuromed IRCCS
• Original Responsible Party: Same as current
• Current Study Sponsor: Neuromed IRCCS
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Teresa Esposito, PhD; IRCCS INM Neuromed

• PRS Account: Neuromed IRCCS
• Verification Date: February 2023