Precision Diagnosis and Therapy for Rare Diseases by Interpreting Non-coding Genomes
Trial statusRecruiting
Trial phaseNot listed
Trial typeObservational
Biological sexAll
AgeNot listed
SponsorIRCCS Azienda Ospedaliero-Universitaria di Bologna
About this trial
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
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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.
Disqualifiers
None
Trial 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.
Trial design
Design model
Other
Time perspective
Cross-sectional
Treatments tested in this trial
PARADIGM study aims to streamline the process from genomic characterization of RGD patients with ED/NMD to identification of the suitable personalized therapy.
GeneticSamples 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.
Treatment groups
100 Participants
are divided into 1 treatment groupGroup A: Genomic characterization of RGD patients with ED/NMD1 intervention
Trial outcomes
Primary outcomes
1
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.
Time frame
22 monthsSecondary 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.
Time frame
24 monthsSponsors and contacts
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Source ClinicalTrials.gov