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  5. COZZOLINO_Therapeutic correction of alternative splicing defects in hnRNPA2/B1 as a way to counteract Amyotrophic Lateral Sclerosis associated to FUS Acronomimo SWITCHALS (DSB.AD007.268)
Research project

COZZOLINO_Therapeutic correction of alternative splicing defects in hnRNPA2/B1 as a way to counteract Amyotrophic Lateral Sclerosis associated to FUS Acronomimo SWITCHALS (DSB.AD007.268)

Thematic area

Biomedical sciences

Project area

Biomedicina Traslazionale (DSB.AD007)

Structure responsible for the research project

Institute of Traslational Pharmacology (IFT)

Project manager

MAURO COZZOLINO
Phone number: 0649934418
Email: mauro.cozzolino@ift.cnr.it

Abstract

Antisense oligonucleotides (ASOs) are a new and highly promising class of drugs for precision medicine. ASOs are short synthetic single-stranded nucleic acids that can modulate gene expression via annealing complementary RNA target sequences. Since altered RNA processing is a hallmark feature of many neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS), ASOs are valuable therapeutic tools for these yet incurable diseases. Data from our lab show that FUS, an RNA-binding protein that is mutated in genetic ALS, induces alternative splicing defects in A2/B1, leading to alterations in the expression, distribution and activity of A2/B1 protein isoforms, that eventually lead to motor neuron degeneration. On these grounds, the aim of this project is to define a therapeutic strategy using splicing switching oligonucleotides (SSOs) to correct splicing defects in A2/B1 as a way to counteract FUS-ALS neurodegeneration. In particular, we will design and validate SSOs based on their ability to modify A2/B1 splicing pattern and test them in FUS-ALS mice in order to evaluate their therapeutic efficacy.

Goals

Specific objectives of this project are:
i. To design and validate in vitro splicing-switching oligonucleotides that can modulate alternative splicing of A2/B1 pre-mRNA and assess their potential therapeutic use in in vitro models that are relevant for the disease;
ii. Assess the ability of the identified SSOs to correct neurodegeneration in mice modeling FUS-ALS.

Start date of activity

01/04/2022

Keywords

sclerosi laterale amiotrofica, metabolismo dell'RNA, Oligonucleotidi antisenso, sclerosi laterale amiotrofica, metabolismo dell'RNA, Oligonucleotidi antisenso, sclerosi laterale amiotrofica, metabolismo dell'RNA, Oligonucleotidi antisenso

Last update: 07/06/2025