Clinical trial NCT05721911: 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
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Parkinson Disease
REM Sleep Behavior Disorder
Lead sponsor: Neuromed IRCCS
Sponsor class: OTHER
First posted: 2023-02-10
Enrollment: 230
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
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

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.

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

Primary outcomes:
measure: motor symptoms of PD and RBD patients will be evaluated with Hoehn and Yahr (HY) score
timeFrame: 2 years
measure: motor and non motor symptoms of PD and RBD patients will be evaluated with MDS-UPDRS
timeFrame: 2 years
measure: clinical evaluation of of sleep disorders in PD and RBD patients
timeFrame: 2 years
measure: clinical evaluation of of sleep disorders in PD and RBD patients by Polysomnography
timeFrame: 2 years
measure: clinical evaluation of cognitive impairment of PD and RBD patients by MoCA test score
timeFrame: 2 years
measure: clinical evaluation of levodopa-induced dyskinesia (LID) in PD patients
timeFrame: 2 years
measure: identification of variants/mutations
timeFrame: 2 years
measure: association with phenotypic manifestation of PD
timeFrame: 2 years
Secondary outcomes:
Other outcomes:
Locations:
city: Pozzilli
country: Italy
facility: IRCCS Neuromed
Study officials:
affiliation: IRCCS INM Neuromed
name: Teresa Esposito, PhD
role: PRINCIPAL_INVESTIGATOR
References: