Neuromuscular DiseasesNCT06775561
Precision Diagnosis and Therapy for Rare Diseases by Interpreting Non-coding Genomes
An observational study of Neuromuscular Diseases and Eye Diseases, run by IRCCS Azienda Ospedaliero-Universitaria di Bologna at 1 site in Italy.
Trial summary
PARADIGM study, funded by the PNRR research grant, will focus on Eye Diseases (ED) and Neuro-Muscular Diseases (NMD) as groups of genetically heterogeneous diseases which are extensively studied by the Partners partecipating in the project; indeed ED and NMD are well clinically and molecularly characterized and… Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Neuromuscular Diseases, Eye Diseases, Genetic Disease
- What is being tested?
- PARADIGM study aims to streamline the process from genomic characterization of RGD patients with ED/NMD to identification of the suitable personalized therapy.
- How many people
- 100 participants
- Where
- 1 siteItaly
- Study dates
- 20 May 2023to 20 May 2025
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Study population: The study population will include: * patients previously in diagnostic routine, who have provided informed consent for storage and secondary use of their biological samples and for being recontacted; they will be informed about the current project and requested to provide a new specific informed consent; * patients' parents and/or other relatives (e.g. siblings, auncle/aunt); * age: from 0 years (newborns) with no upper age limit.
Who may be able to join
- patients/relatives of patients with clinical diagnosis of NMD/ED;
- patients/relatives of patients with inconclusive ES and aCGH data (no pathogenic/likely pathogenic variant) or finding of only a single hit (a pathogenic or likely pathogenic variant) in an autosomal recessive gene by ES (or aCGH) or no pathogenic or likely pathogenic variant but detection of a large region of genomic homozygosity surrounding a candidate gene;
- patients/relatives of patients with a finding of cryptic VUS (splicing/regulatory/noncoding CNVs) in ED/NMD genes or pathogenic cryptic variants in a selected number of representative cases.
- Signed informed consent to participate in the study.
Who cannot join
- Trios or nuclear families where both unaffected parents do not consent to participate will be excluded (similarly, a minimum number of 3 affected family members will be needed in multigenerational pedigrees).
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Italy1 site, 1 recruiting
- Recruiting
IRCCS Azienda Ospedaliero-Universitaria di Bologna
Bologna, 40138
Tommaso Pippucci, Biologist, +390512142892, tommaso.pippucci@unibo.it
Tommaso Pippucci, Biologist
About this study
Official title: Precision Diagnosis and Therapy for Rare Diseases by Interpreting Non-coding Genomes (PARADIGM)
PARADIGM study, funded by the PNRR research grant, will focus on Eye Diseases (ED) and Neuro-Muscular Diseases (NMD) as groups of genetically heterogeneous diseases which are extensively studied by the Partners partecipating in the project; indeed ED and NMD are well clinically and molecularly characterized and approachable by drug-testing options already assessed and implemented by PARADIGM partners. ED and NMD represent good and compatible disease models as:
- both are genetically heterogeneous disorders where missing heritability is likely to be hidden in non-coding variants;
- many of the individual genes accountable for the ED and NMD cause autosomal recessive forms, increasing the chance of finding regulatory/splicing variants
Read the detailed description
UO1 (IRCCS Azienda Ospedaliero-Universitaria di Bologna, Coordinator) will coordinate the data collection and management protocols under fundamental ethical principles and relevant national, EU and international legislation; will set-up the bioinformatic data warehouse and deploy the workflows to analyze omics data analysis applying its own and published bioinformatic pipelines and will contribute to multi-omics data analysis.
UO2 (IRCCS Fondazione Istituto Neurologico Casimiro Mondino, Partner) will perform HiC/UMI-4C analyses and will contribute to the identification, validation and characterization of non-coding variants associated with RGDs, providing cellular and molecular genetic tools for the project to be tested in vitro or on patients' cell cultures from blood or skin. Only in specific cases (e.g. genes selectively expressed in the affected tissue), induced pluripotent stem cells (iPSCs) started from patients' fibroblasts will be used to generate 2D/3D cell models (e.g. retinal organoids) differentiated into the tissue of interes to dissect the molecular basis of unresolved RGDs.
UO3 (Azienda Ospedaliero-universitaria Luigi Vanvitelli, Partner) will carry out and integrate Genome Sequencing (GS) and transcriptome analysis on RNA from accessible tissues, e.g., cultured peripheral blood mononuclear cells (PBMCs), cultured fibroblasts (or fibroblast derived organoids), skeletal muscle (only when available in diagnostic routine).
UO4 (Università degli Studi di Napoli Federico II) will develop state-of-art gene therapy approaches to correct non-coding variants associated with RGDs, and test their efficiency in relevant retinal organoid models.
UO1, UO2, UO3 will be the clinical centers for recruitment of patients and collection of samples. This partnership gathers experts in the main omics, clinical geneticists, molecular biologists, and gene therapists, with massive experience in handling omics data, characterizing genetic variants for clinical purpose and developing therapeutics for genetic diseases up to the clinical stage.
- Conditions
- Neuromuscular Diseases, Eye Diseases, Genetic Disease
- Being tested
- PARADIGM study aims to streamline the process from genomic characterization of RGD patients with ED/NMD to identification of the suitable personalized therapy.
- Medical subject headings
- Neuromuscular Diseases, Eye Diseases, Genetic Diseases, Inborn
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PARADIGM study aims to streamline the process from genomic characterization of RGD patients with ED/NMD to identification of the suitable personalized therapy.Genetic
Samples are collected by UO1/UO2/UO3. DNA/RNA samples are sent to UO3 for genome and transcriptome sequencing. In vitro systems or patient-derived cell models are used for in vitro experimental validation (UO2) or development of therapeutical approaches (UO2/UO4). Samples of cases still undiagnosed after the combined sequencing and validation approaches undergo long-read sequencing by an outsourcing facility. Sequencing data are transferred to UO1 for bioinformatic analysis and may be deposited into RDconnect for still inconclusive cases. Variants of interest from bioinformatic analyses and in vitro validations are collectively discussed by UO1/UO2/UO3 to evaluate their clinico-molecular significance and to be selected for testing therapeutic approaches by UO2/UO4. Blue arrows and shapes denote samples and personal data, while green data that make no identifiable person.
| Study group | Role | What they receive |
|---|---|---|
| Genomic characterization of RGD patients with ED/NMD | * patients/relatives or parents of patients with a clinical diagnosis of rare eye and neuromuscular diseases
* patients/relatives or parents of patients with inconclusive data from ESOMA and aCGH (no pathogenic/probable pathogenic variant) or detection of a single hit (a pathogenic or probable pathogenic variant) in an autosomal recessive gene from ESOMA (or aCGH) or no pathogenic or probable pathogenic variant but detection of a large region of genomic homozygosity surrounding a candidate gene
* patients/relatives or parents of patients with detection of cryptic VUS (variants of uncertain significance) (splicing/regulatory/non-coding CNVs) in candidate genes or pathogenic cryptic variants in a selected number of representative cases. Receives: Genetic: PARADIGM study aims to streamline the process from genomic characterization of RGD patients with ED/NMD to identification of the suitable personalized therapy. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Identification of genomic variants
To efficiently and reliably identify, and clinically interpret, cryptic genomic variants, representing the central challenge for the next decades of human genetics. The study will focus on ED and NMD conditions. The Diagnostic yield will be calculated as the proportion of the diagnosed cases over the total cases. Cases will be considered to be diagnosed when pathogenic or likely pathogenic genotype(s) will be identified and will be consistent with the patients clinical phenotype and segregation in the family.
Measured: 22 months
Secondary outcomes (1)
Evaluation of therapeutic efficiency
To develop and validate the preferred strategy for a treatment based on RNA therapeutics, CRISPR/Cas9-mediated genome editing or drug-repositioning. The therapeutic efficiency will be evaluated by transfection in HEK293 cells both at the DNA, RNA and protein level and the most efficient approach will be further side-by-side tested in 3D retinal organoids, in order to evaluate in more relevant models their ability to rescue the splicing defect as well as to ameliorate disease-specific morphological alterations.
Measured: 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Jan 2025
- Study start20 May 2023
- Primary completion20 May 2025 (estimated)
- Study completion20 May 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Neuromuscular DiseasesStudies of the same condition, open and under way.
- More trials run by IRCCS Azienda Ospedaliero-Universitaria di BolognaThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Other
- Time perspective
- Cross-sectional
- Enrolment
- 100 participants (estimated)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Tommaso Pippucci, Biologist, Principal investigator, IRCCS Azienda Ospedaliero-Universitaria di Bologna
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06775561
- Sponsor's protocol ID
- PARADIGM
- Other IDs
- PNRR: M6/C2_CALL 2022
- Status last verified
- Nov 2024
- First submitted
- 28 Nov 2024
- Last updated
- 15 Jan 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 15 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Precision Diagnosis and Therapy for Rare Diseases by Interpreting Non-coding Genomes (PARADIGM)
- ClinicalTrials.gov ID
- NCT06775561
- Acronym / sponsor ID
- PARADIGM
- Conditions
- Neuromuscular Diseases, Eye Diseases, Genetic Disease
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 100 participants (estimated)
- Lead sponsor
- IRCCS Azienda Ospedaliero-Universitaria di BolognaUniversity, hospital or other
- Study start
- 20 May 2023 (actual)
- Primary completion
- 20 May 2025 (estimated)
- Study completion
- 20 May 2025 (estimated)
- First posted
- 15 Jan 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
PARADIGM study, funded by the PNRR research grant, will focus on Eye Diseases (ED) and Neuro-Muscular Diseases (NMD) as groups of genetically heterogeneous diseases which are extensively studied by the Partners partecipating in the project; indeed ED and NMD are well clinically and molecularly characterized and approachable by drug-testing options already assessed and implemented by PARADIGM partners. ED and NMD represent good and compatible disease models as:
- both are genetically heterogeneous disorders where missing heritability is likely to be hidden in non-coding variants;
- many of the individual genes accountable for the ED and NMD cause autosomal recessive forms, increasing the chance of finding regulatory/splicing variants
Detailed description
UO1 (IRCCS Azienda Ospedaliero-Universitaria di Bologna, Coordinator) will coordinate the data collection and management protocols under fundamental ethical principles and relevant national, EU and international legislation; will set-up the bioinformatic data warehouse and deploy the workflows to analyze omics data analysis applying its own and published bioinformatic pipelines and will contribute to multi-omics data analysis.
UO2 (IRCCS Fondazione Istituto Neurologico Casimiro Mondino, Partner) will perform HiC/UMI-4C analyses and will contribute to the identification, validation and characterization of non-coding variants associated with RGDs, providing cellular and molecular genetic tools for the project to be tested in vitro or on patients' cell cultures from blood or skin. Only in specific cases (e.g. genes selectively expressed in the affected tissue), induced pluripotent stem cells (iPSCs) started from patients' fibroblasts will be used to generate 2D/3D cell models (e.g. retinal organoids) differentiated into the tissue of interes to dissect the molecular basis of unresolved RGDs.
UO3 (Azienda Ospedaliero-universitaria Luigi Vanvitelli, Partner) will carry out and integrate Genome Sequencing (GS) and transcriptome analysis on RNA from accessible tissues, e.g., cultured peripheral blood mononuclear cells (PBMCs), cultured fibroblasts (or fibroblast derived organoids), skeletal muscle (only when available in diagnostic routine).
UO4 (Università degli Studi di Napoli Federico II) will develop state-of-art gene therapy approaches to correct non-coding variants associated with RGDs, and test their efficiency in relevant retinal organoid models.
UO1, UO2, UO3 will be the clinical centers for recruitment of patients and collection of samples. This partnership gathers experts in the main omics, clinical geneticists, molecular biologists, and gene therapists, with massive experience in handling omics data, characterizing genetic variants for clinical purpose and developing therapeutics for genetic diseases up to the clinical stage.
Study design
- Observational model
- Other
- Time perspective
- Cross-sectional
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Genomic characterization of RGD patients with ED/NMD | – | Genetic: PARADIGM study aims to streamline the process from genomic characterization of RGD patients with ED/NMD to identification of the suitable personalized therapy.* patients/relatives or parents of patients with a clinical diagnosis of rare eye and neuromuscular diseases * patients/relatives or parents of patients with inconclusive data from ESOMA and aCGH (no pathogenic/probable pathogenic variant) or detection of a single hit (a pathogenic or probable pathogenic variant) in an autosomal recessive gene from ESOMA (or aCGH) or no pathogenic or probable pathogenic variant but detection of a large region of genomic homozygosity surrounding a candidate gene * patients/relatives or parents of patients with detection of cryptic VUS (variants of uncertain significance) (splicing/regulatory/non-coding CNVs) in candidate genes or pathogenic cryptic variants in a selected number of representative cases. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
- Study population
- The study population will include: * patients previously in diagnostic routine, who have provided informed consent for storage and secondary use of their biological samples and for being recontacted; they will be informed about the current project and requested to provide a new specific informed consent; * patients' parents and/or other relatives (e.g. siblings, auncle/aunt); * age: from 0 years (newborns) with no upper age limit.
Key inclusion criteria (4 listed)
- patients/relatives of patients with clinical diagnosis of NMD/ED;
- patients/relatives of patients with inconclusive ES and aCGH data (no pathogenic/likely pathogenic variant) or finding of only a single hit (a pathogenic or likely pathogenic variant) in an autosomal recessive gene by ES (or aCGH) or no pathogenic or likely pathogenic variant but detection of a large region of genomic homozygosity surrounding a candidate gene;
- patients/relatives of patients with a finding of cryptic VUS (splicing/regulatory/noncoding CNVs) in ED/NMD genes or pathogenic cryptic variants in a selected number of representative cases.
- Signed informed consent to participate in the study.
Key exclusion criteria (1 listed)
- Trios or nuclear families where both unaffected parents do not consent to participate will be excluded (similarly, a minimum number of 3 affected family members will be needed in multigenerational pedigrees).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PARADIGM study aims to streamline the process from genomic characterization of RGD patients with ED/NMD to identification of the suitable personalized therapy.Samples are collected by UO1/UO2/UO3. DNA/RNA samples are sent to UO3 for genome and transcriptome sequencing. In vitro systems or patient-derived cell models are used for in vitro experimental validation (UO2) or development of therapeutical approaches (UO2/UO4). Samples of cases still undiagnosed after the combined sequencing and validation approaches undergo long-read sequencing by an outsourcing facility. Sequencing data are transferred to UO1 for bioinformatic analysis and may be deposited into RDconnect for still inconclusive cases. Variants of interest from bioinformatic analyses and in vitro validations are collectively discussed by UO1/UO2/UO3 to evaluate their clinico-molecular significance and to be selected for testing therapeutic approaches by UO2/UO4. Blue arrows and shapes denote samples and personal data, while green data that make no identifiable person. | Genetic | Genomic characterization of RGD patients with ED/NMD |
Primary outcome
Identification of genomic variants
Time frame: 22 months
To efficiently and reliably identify, and clinically interpret, cryptic genomic variants, representing the central challenge for the next decades of human genetics. The study will focus on ED and NMD conditions. The Diagnostic yield will be calculated as the proportion of the diagnosed cases over the total cases. Cases will be considered to be diagnosed when pathogenic or likely pathogenic genotype(s) will be identified and will be consistent with the patients clinical phenotype and segregation in the family.
1 secondary outcome
Evaluation of therapeutic efficiency
Time frame: 24 months
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Jan 2025.
- Individual participant dataSharing planned: No
Related trials for Neuromuscular Diseases
Active, not recruitingPhase 1/2
Selumetinib in Treating Young Patients With Recurrent or Refractory Low Grade Glioma
Low Grade Glioma, Recurrent Childhood Pilocytic Astrocytoma
Enrolling by invitation
Online Exercise Program for Transplant Patients: A Pilot Study
Kidney Transplantation, Physical Function
Active, not recruitingPhase 4
A Study Evaluating the Effectiveness and Safety of Risdiplam Administered as an Early Intervention in Pediatric Participants With Spinal Muscular Atrophy After Gene Therapy
Muscular Atrophy, Spinal
RecruitingObservational study
Pain Phenotypes in Individuals With Multiple Sclerosis
Multiple Sclerosis, Chronic Pain
Not yet recruitingPhase 2
A Study of Bimagrumab in Participants With HFpEF
Heart Failure, Diastolic, Diastolic Heart Failure
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Tommaso Pippucci, Biologist principal investigator
IRCCS Azienda Ospedaliero-Universitaria di Bologna
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Neuromuscular Diseases and Eye Diseases, run by IRCCS Azienda Ospedaliero-Universitaria di Bologna at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 15 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Tommaso Pippucci, Biologist (0512142892, tommaso.pippucci@unibo.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Identification of genomic variants (time frame: 22 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Jan 2025.