Universität zu Köln

Torres-Benito, Laura, Schneider, Svenja, Rombo, Roman, Ling, Karen K., Grysko, Vanessa, Upadhyay, Aaradhita, Kononenko, Natalia L., Rigo, Frank, Bennett, C. Frank and Wirth, Brunhilde ORCID: 0000-0003-4051-5191 (2019). NCALD Antisense Oligonucleotide Therapy in Addition to Nusinersen further Ameliorates Spinal Muscular Atrophy in Mice. Am. J. Hum. Genet., 105 (1). S. 221 - 231. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

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Abstract

Spinal muscular atrophy (SMA) is a neuromuscular disease causing the most frequent genetic childhood lethality. Recently, nusinersen, an antisense oligonucleotide (ASO) that corrects SMN2 splicing and thereby increases full-length SMN protein, has been approved by the FDA and EMA for SMA therapy. However, the administration of nusinersen in severe and/or post-symptomatic SMA-affected individuals is insufficient to counteract the disease. Therefore, additional SMN-independent therapies are needed to support the function of motoneurons and neuromuscular junctions. We recently identified asymptomatic SMN1-deleted individuals who were protected against SMA by reduced expression of neurocalcin delta (NCALD). NCALD reduction is proven to be a protective modifier of SMA across species, including worm, zebrafish, and mice. Here, we identified Ncald-ASO3-out of 450 developed Ncald ASOs-as the most efficient and non-toxic ASO for the CNS, by applying a stepwise screening strategy in cortical neurons and adult and neonatal mice. In a randomized-blinded preclinical study, a single subcutaneous low-dose SMN-ASO and a single intracerebroventricular Ncald-ASO3 or control-ASO injection were presymptomatically administered in a severe SMA mouse model. NCALD reduction of >70% persisted for about 1 month. While low-dose SMN-ASO rescues multiorgan impairment, additional NCALD reduction significantly ameliorated SMA pathology including electrophysiological and histological properties of neuromuscular junctions and muscle at P21 and motoric deficits at 3 months. The present study shows the additional benefit of a combinatorial SMN-dependent and SMN-independent ASO-based therapy for SMA. This work illustrates how a modifying gene, identified in some asymptomatic individuals, helps to develop a therapy for all SMA-affected individuals.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Torres-Benito, Laura UNSPECIFIED UNSPECIFIED UNSPECIFIED Schneider, Svenja UNSPECIFIED UNSPECIFIED UNSPECIFIED Rombo, Roman UNSPECIFIED UNSPECIFIED UNSPECIFIED Ling, Karen K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Grysko, Vanessa UNSPECIFIED UNSPECIFIED UNSPECIFIED Upadhyay, Aaradhita UNSPECIFIED UNSPECIFIED UNSPECIFIED Kononenko, Natalia L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rigo, Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Bennett, C. Frank UNSPECIFIED UNSPECIFIED UNSPECIFIED Wirth, Brunhilde UNSPECIFIED orcid.org/0000-0003-4051-5191 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-135600
DOI:	10.1016/j.ajhg.2019.05.008
Journal or Publication Title:	Am. J. Hum. Genet.
Volume:	105
Number:	1
Page Range:	S. 221 - 231
Date:	2019
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1537-6605
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language MOUSE MODEL; SHAM CONTROL; PLASTIN 3; SMA; PHENOTYPE; DIAGNOSIS; SURVIVAL; RESTORATION; MANAGEMENT; RESCUES Multiple languages Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/13560