Gene editing potential treatment for rare muscular dystrophy LGMD D2 developed

(From left to right). Jorge Espinosa, Águeda Blázquez and Rubén Artero.
(From left to right). Jorge Espinosa, Águeda Blázquez and Rubén Artero.

Researchers from the IIS La Fe of Valencia and the Centre for Network Biomedical Research in Rare Diseases (CIBERER), in collaboration with the BIOTECMED Institute of the University of Valencia and the INCLIVA Health Research Institute, have managed to correct with gene editing technology CRISPR-Cas9 mutation of the gene causing LGMD D2 muscular dystrophy in cells of patients affected by this disorder, also known as transportin muscular dystrophy.

Of the approximately 100 cases of this ultra-rare disease that are known in the world, 90 are located in Spain. The results of this research are presented as a potential treatment for this disease. The disease is characterised by progressive muscular paralysis with a wide variability regarding the age of onset, evolution and severity.

The gene that carries the mutation that causes this disease (TNPO3) encodes a protein that is responsible for introducing other proteins related to the metabolism of nucleic acids into the cell nucleus and is also involved in other diseases such as HIV infection (AIDS).

The study was carried out on immortalised muscle cells from a patient suffering from the disease. The research, published in the journal Molecular Therapy - Nucleic Acids, has shown that treated diseased cells regained vitality, corrected various altered functions such as autophagy, and largely recovered previously altered cell function.

In the research, in which from the BIOTECMED Translational Genomics Group Águeda Blázquez, Jorge Espinosa and Rubén Artero participate, has collaborated with the European Reference Unit for Rare Neuromuscular Diseases of the La Fe University Hospital in Valencia, the Pathology Research Group Neuromuscular of the IIS La Fe and the Unit of Molecular, Cellular and Genomic Biomedicine of this same institute, both integrated in the Centre for Biomedical Research in Rare Diseases Network (CIBERER).

LGMD D2 muscular dystrophy is an ultra-rare disease with a special incidence in Spain. The 90 cases diagnosed in our country belong to a lineage whose common ancestor inhabited 8 generations ago in a town in the interior of the Murcia region. "The pathogenic mechanisms of this disease are unknown, but this study can help to discover them", highlights the coordinator of the study, Juan Jesús Vílchez, a researcher at IIS La Fe and CIBERER.

This research has received substantial funding from the Conquistando Escalones association for patients with this disease. To get started, the project also received support from the CIBERER Collaborative Intramural Cooperative Actions (ACCI) program. Subsequently, it has been supported with grants from the FEDER Foundation and the Ministry of Science and Innovation.

The Centre for Network Biomedical Research (CIBER) is a consortium dependent on the Carlos III Health Institute (Ministry of Science and Innovation) and is co-funded by the European Regional Development Fund (FEDER). The CIBER in its Thematic Area of Rare Diseases (CIBERER) is the reference centre in Spain for research on rare diseases.

Article : Javier Poyatos-García, Águeda Blázquez-Bernal, Marta Selva-Giménez, Ariadna Bargiela, Jorge Espinosa-Espinosa, Rafael P. Vázquez-Manrique, Anne Bigot, Rubén Artero, Juan Jesús Vílchez. ’CRISPR-Cas9 editing of a TNPO3 mutation in a muscle cell model of limb-girdle muscular dystrophy type D2’. Molecular Therapy - Nucleic Acids. Volume 31, 14 March 2023, Pages 324’338 . DOI:­023.01.004