Biomaterial Database

Tetracyclines that promote SMN2 exon 7 splicing as therapeutics for spinal muscular atrophy. 2009

Michelle L Hastings, and Joel Berniac, and Ying Hsiu Liu, and Paul Abato, and Francine M Jodelka, and Lea Barthel, and Sujatha Kumar, and Caroline Dudley, and Mark Nelson, and Kelley Larson, and Jason Edmonds, and Todd Bowser, and Michael Draper, and Paul Higgins, and Adrian R Krainer

Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60044, USA. michelle.hastings@rosalindfranklin.edu

There is at present no cure or effective therapy for spinal muscular atrophy (SMA), a neurodegenerative disease that is the leading genetic cause of infant mortality. SMA usually results from loss of the SMN1 (survival of motor neuron 1) gene, which leads to selective motor neuron degeneration. SMN2 is nearly identical to SMN1 but has a nucleotide replacement that causes exon 7 skipping, resulting in a truncated, unstable version of the SMA protein. SMN2 is present in all SMA patients, and correcting SMN2 splicing is a promising approach for SMA therapy. We identified a tetracycline-like compound, PTK-SMA1, which stimulates exon 7 splicing and increases SMN protein levels in vitro and in vivo in mice. Unlike previously identified molecules that stimulate SMN production via SMN2 promoter activation or undefined mechanisms, PTK-SMA1 is a unique therapeutic candidate in that it acts by directly stimulating splicing of exon 7. Synthetic small-molecule compounds such as PTK-SMA1 offer an alternative to antisense oligonucleotide therapies that are being developed as therapeutics for a number of disease-associated splicing defects.

UI	MeSH Term	Description	Entries
D009134	Muscular Atrophy, Spinal	A group of disorders marked by progressive degeneration of motor neurons in the spinal cord resulting in weakness and muscular atrophy, usually without evidence of injury to the corticospinal tracts. Diseases in this category include Werdnig-Hoffmann disease and later onset SPINAL MUSCULAR ATROPHIES OF CHILDHOOD, most of which are hereditary. (Adams et al., Principles of Neurology, 6th ed, p1089)	Bulbospinal Neuronopathy,Oculopharyngeal Spinal Muscular Atrophy,Progressive Muscular Atrophy,Scapuloperoneal Form of Spinal Muscular Atrophy,Spinal Muscular Atrophy,Adult Spinal Muscular Atrophy,Adult-Onset Spinal Muscular Atrophy,Amyotrophy, Neurogenic Scapuloperoneal, New England Type,Distal Spinal Muscular Atrophy,Hereditary Motor Neuronopathy,Muscular Atrophy, Adult Spinal,Myelopathic Muscular Atrophy,Myelopathic Muscular Atrophy, Progressive,Progressive Myelopathic Muscular Atrophy,Progressive Proximal Myelopathic Muscular Atrophy,Proximal Myelopathic Muscular Atrophy, Progressive,Scapuloperoneal Spinal Muscular Atrophy,Spinal Amyotrophy,Spinal Muscular Atrophy, Distal,Spinal Muscular Atrophy, Oculopharyngeal,Spinal Muscular Atrophy, Scapuloperoneal,Spinal Muscular Atrophy, Scapuloperoneal Form,Adult Onset Spinal Muscular Atrophy,Amyotrophies, Spinal,Amyotrophy, Spinal,Atrophies, Progressive Muscular,Atrophy, Myelopathic Muscular,Atrophy, Progressive Muscular,Atrophy, Spinal Muscular,Bulbospinal Neuronopathies,Hereditary Motor Neuronopathies,Motor Neuronopathies, Hereditary,Motor Neuronopathy, Hereditary,Muscular Atrophies, Progressive,Muscular Atrophy, Myelopathic,Muscular Atrophy, Progressive,Neuronopathies, Bulbospinal,Neuronopathies, Hereditary Motor,Neuronopathy, Bulbospinal,Neuronopathy, Hereditary Motor,Progressive Muscular Atrophies,Spinal Amyotrophies
D005091	Exons	The parts of a transcript of a split GENE remaining after the INTRONS are removed. They are spliced together to become a MESSENGER RNA or other functional RNA.	Mini-Exon,Exon,Mini Exon,Mini-Exons
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D012326	RNA Splicing	The ultimate exclusion of nonsense sequences or intervening sequences (introns) before the final RNA transcript is sent to the cytoplasm.	RNA, Messenger, Splicing,Splicing, RNA,RNA Splicings,Splicings, RNA
D013754	Tetracyclines	Closely congeneric derivatives of the polycyclic naphthacenecarboxamide. (Gilman et al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed, p1117)
D051379	Mice	The common name for the genus Mus.	Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D055540	Survival of Motor Neuron 2 Protein	An SMN complex protein that is closely-related to SURVIVAL OF MOTOR NEURON 1 PROTEIN. In humans, the protein is encoded by an often duplicated gene found near the inversion CENTEROMERE of a large inverted region of CHROMOSOME 5.	Survival Motor Neuron Protein 2,Survival of Motor Neuron 2, Centromeric Protein,Survival of Motor Neuron 3, Centromeric Protein