Assessment of Nuclear Gem Quantity for Evaluating the Efficacy of Antisense Oligonucleotides in Spinal Muscular Atrophy Cells

Author:

Al-Hilal Haya12,Maretina Marianna1,Egorova Anna1,Glotov Andrey1ORCID,Kiselev Anton1ORCID

Affiliation:

1. Department of Genomic Medicine Named after V.S. Baranov, D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, Mendeleevskaya Line 3, 199034 Saint-Petersburg, Russia

2. Faculty of Biology, Saint-Petersburg State University, Universitetskaya Embankment 7-9, 199034 Saint-Petersburg, Russia

Abstract

Spinal muscular atrophy is a neuromuscular disorder caused by mutations in both copies of the survival motor neuron gene 1 (SMN1), which lead to reduction in the production of the SMN protein. Currently, there are several therapies that have been approved for SMA, with many more undergoing active research. While various biomarkers have been proposed for assessing the effectiveness of SMA treatment, a universally accepted one still has not been identified. This study aimed to describe a fast and reliable method using the number of gems in cell nuclei as a potential tool for assessment of splicing correction of oligonucleotide efficacy in SMA cells. To gain insight into whether the number of gems in cell nuclei varies based on their SMN genotype and whether the increase in gem number is associated with therapeutic response, we utilized fibroblast cell cultures obtained from a patient with SMA type II and from a healthy individual. We discovered a remarkable difference in the number of gems found in the nuclei of these cells, specifically when counting gems per 100 nuclei. The SMA fibroblasts treated with antisense oligonucleotide showed beneficial effects in correcting the abnormal splicing of SMN2 exon 7. It was observed that there was a significant increase in the number of gems in the treated cells compared to the intact SMA cells. The results obtained significantly correlate with an increase of full-length SMN transcript sharing. Based on our findings, we propose using the quantity of gems as a reliable biomarker for SMA drug development.

Funder

Ministry of Science and Higher Education of the Russian Federation

Publisher

MDPI AG

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