SMN Circular RNAs as Potential Biomarkers for the Therapeutic Response to Nusinersen in Spinal Muscular Atrophy Patients

NCT05761262 | Unknown

• 1 other identifier: 2614
• Study Type: observational
• Target: 91
• Locations: 1 country
• Sites: 1

Brief Summary

The first cure for Spinal Muscular Atrophy (SMA; Nusinersen) has been approved by FDA in 2017. Although it improves the clinical picture of most SMA patients, not all exhibit the same response to treatment. In this project the aim will be: i. identifying cell-free SMN circular RNAs (circRNAs) in body fluids of SMA patients as potential biomarkers before and after Nusinersen; ii. evaluating their prognostic power as predictors of the clinical response of SMA patients to Nusinersen; iii. identifying human intronic polymorphisms that affect SMN circRNAs biogenesis and impact on the efficacy of Nusinersen. The results obtainable with this project will evaluate if different concentration of cell free SMN circRNAs in SMA patients could underlie the genotype-phenotype mismatch, usually observed, and the reduced response of a subset of SMA patients to therapy. Our research could highlight the need for these of combinatorial 'SMN-plus' and "personalized" therapies that account for individual differences.

Conditions

Spinal Muscular Atrophy

Outcome Measures

Primary Outcomes (3)

• Identification of cell-free SMN circRNAs in body fluids of SMA patients as potential biomarkers before and after Nusinersen treatment

  We will test the expression of cell-free SMN circRNAs and we will evaluate the correlation between SMN circRNA concentration and disease severity. In parallel, we will evaluate the expression level of SMN2 linear transcripts in peripheral blood mononucleated cells (PBMCs) for each patient to assess whether linear SMN2 mRNA expression is inversely related to SMN circRNA biogenesis and whether this parameter accounts for SMN expression and disease severity independently of SMN2 copy number. Once we select the SMN circRNAs with the highest prognostic power, we will use them as potential biomarkers of response to therapy. To this end, we will evaluate whether the concentration of SMN circRNAs varies over time in Nusinersen-treated SMA patients by measuring their concentration in body fluids before and after 6 months of drug administration, according to standard therapeutic regimen in use in our Unit.

  36 months

• Evaluation of prognostic power of circulating SMN circRNAs as predictors of the clinical response of SMA patients to Nusinersen

  In light of this, SMA patients with same eligibility criteria (SMN2 copy number, onset and clinical symptoms) will be stratified into three subgroups based on the concentration of circulating cell-free SMN circRNAs (high, intermediate and low) and their responsiveness to the Nusinersen will be evaluated after the 5th injection of the drug (6 months after the first administration). Evaluation criteria of treatment efficacy consist in HINE (Hammersmith Infant Neurological Examination) and CHOP INTEND (Children Hospital Of Philadelphia Infant Test of Neuromuscular Disorder) for SMA type-I, in neurological examination and HFMSE (Hammersmith Functional Motor Scale-Expandend) for type-II and in neurological examination, HFMSE and 6MWT (6 Minute Walk Test) for type-III patients. This study could also benefit of retrospective analyses already performed by our Unit

  36 months

• Identification of human intronic polymorphisms present within inverted Alu elements and their impact on the efficacy of Nusinersen treatment

  The inverse correlation between the number of SMN2 copy and disease severity is not observed in all SMA patients. Moreover, not all SMA patients respond similarly to Nusinersen therapy. On the basis of the competition between linear and circular processing of SMN pre-mRNA, we intend to evaluate whether a differential SMN circularization index (understood as propensity of SMN pre-mRNA to circulate) could underlie these observed discrepancies. To this aim, we will perform Next Generation Sequencing analysis (Genosplice, Paris, France) of the entire SMN2 gene from genomic DNA of \~100 patients in which the SMN2 gene copy number does not correlate with phenotypic severity or whose response to Nusinersen treatment is below expectation. In particular, we will focus on intronic SMN2 polymorphisms harbored in inverted Alu elements, which could affect the circularization index of SMN2 pre-mRNA.

  36 months

Study Arms (3)

PATIENTS WITH SMA TYPE I

PATIENTS WITH SMA TYPE II

PATIENTS WITH SMA TYPE III

Eligibility Criteria

• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

All type of SMA patients treated with Nusinersen without age restrictions

You may qualify if:

• patients with genetic diagnosis of SMA treated with Nusinersen
• patients/caregivers that can sign the informed consent

You may not qualify if:

• patients/caregivers inable to sign the informed consent
• patients enrolled in clinical trial
• patients treated with other drug than Nusinersen

Sponsors & Collaborators

• Fondazione Policlinico Universitario Agostino Gemelli IRCCS: lead

Study Sites (1)

ethics committee of IRCCS Fondazione Policlinico Gemelli

Rome, Italy/rome, 00168, Italy

RECRUITING

MeSH Terms

Conditions

Muscular Atrophy, Spinal

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases

Study Officials

• Maria Carmela Pera, PhD

  IRCCS POLICLINICO UNIVERSITARIO A.GEMELLI

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Maria Carmela Pera, PhD

CONTACT

3409177653; mariacarmela.pera@policlinicogemelli.it

VITTORIA PAGLIARINI, PhD

CONTACT

vittoria.pagliarini@unicatt.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: RESEARCHER

Study Record Dates

• First Submitted: February 27, 2023
• First Posted: March 9, 2023
• Study Start: December 13, 2019
• Primary Completion: April 13, 2024
• Study Completion: April 13, 2024
• Last Updated: March 14, 2023

Record last verified: 2023-02

Locations

IT (1)