Profile
Molecular basis of spinal muscular atrophy; RNA processing; gene therapy.
Spinal muscular atrophy (SMA) is an autosomal recessive disorder that is the leading genetic cause of infantile death. SMA is the most common inherited motor neuron disease and occurs in approximately 1:6,000 live births. The gene responsible for SMA is called survival motor neuron-1 (SMN1). Interestingly, a human-specific copy gene is present on the same region of chromosome 5q called SMN2. SMN2 is nearly identical to SMN1, however, mutations in SMN2 have no clinical consequence if SMN1 is retained. The reason why SMN2 cannot prevent disease development in the absence of SMN1 is that the majority of SMN2-derived transcripts are alternatively spliced, resulting in a truncated protein that lacks the 16 amino acids encoded by SMN exon 7 (normally the last coding exon). A single non-polymorphic nucleotide difference (C6T) between SMN1 and SMN2 is responsible for the alternative splicing of the SMN transcripts, however, this is a silent mutation that does not alter the overlapping protein coding capacity of SMN2. Numerous studies have shown that the SMN2-derived protein product (called SMN D 7) is unstable and dysfunctional, further demonstrating the critical nature of the SMN exon 7 splice site decision.
Lab information
Academic Information
Director, Spinal Cord Injury, Disease and Repair Program
Associate Dean for Research and Graduate Studies, College of Veterinary Medicine
Associate Vice Chancellor for Research
Professor, Molecular Microbiology and Immunology
Curators Distinguished Professor
Office
471G Bond Life Sciences Center
Columbia, MO 65211
United States
P. 573-884-2219
Research Interests
- Molecular basis of spinal muscular atrophy
- RNA processing
- Gene therapy
Areas of Expertise
- Virology and Molecular Therapies
- Biophysics
- Developmental Biology
- Gene Expression
- Gene Therapy
- Neuromuscular biology
- RNA Biology
- Bacteriology
- Biochemistry
- Virology
Related Links
Education & Training
Post-Graduate School
1997, PhD, University of Missouri - Columbia
In the News
SMA Clinical Trials Panel at April 2016 FightSMA Conference
Publications
- Shababi M, Smith CE, Kacher M, Alrawi Z, Villalón E, Davis D, Bryda EC, Lorson CL. Development of a novel severe mouse model of spinal muscular atrophy with respiratory distress type 1: FVB-nmd. Biochem Biophys Res Commun. 2019 Oct 8. pii: S0006-291X(19)31921-7. doi: 10.1016/j.bbrc.2019.10.032. [Epub ahead of print]
- Villalón E, Kline RA, Smith CE, Lorson ZC, Osman EY, O'Day S, Murray LM, Lorson CL. AAV9-Stathmin1 gene delivery improves disease phenotype in an intermediate mouse model of Spinal Muscular Atrophy. Hum Mol Genet. 2019 Jul 31. pii: ddz188. doi: 10.1093/hmg/ddz188. [Epub ahead of print]
- Osman EY, Bolding MR, Villalón E, Kaifer KA, Lorson ZC, Tisdale S, Hao Y, Conant GC, Pires JC, Pellizzoni L, Lorson CL. Functional characterization of SMN evolution in mouse models of SMA. Sci Rep. 2019 Jul 1;9(1):9472. doi: 10.1038/s41598-019-45822-8.
- Villalón E, Lee NN, Marquez J, Lorson CL. Muscle fiber-type selective propensity to pathology in the nmd mouse model of SMARD1. Biochem Biophys Res Commun. 2019 Aug 13;516(1):313-319. doi: 10.1016/j.bbrc.2019.06.117. Epub 2019 Jun 28.
- Kaifer KA, Villalón E, O'Brien BS, Sison SL, Smith CE, Simon ME, Marquez J, O'Day S, Hopkins AE, Neff R, Rindt H, Ebert AD, Lorson CL. AAV9-Mediated Delivery of miR-23a Reduces Disease Severity in Smn2B-/SMA Model Mice. Hum Mol Genet. 2019 Jun 18. pii: ddz142. doi: 10.1093/hmg/ddz142. [Epub ahead of print]
- Osman EY, Rietz A, Kline RA, Cherry JJ, Hodgetts KJ, Lorson CL, Androphy EJ. Intraperitoneal delivery of a novel drug-like compound improves disease severity in severe and intermediate mouse models of Spinal Muscular Atrophy. Sci Rep. 2019 Feb 7;9(1):1633. doi: 10.1038/s41598-018-38208-9.
- Shababi M, Villalón E, Kaifer KA, DeMarco V, Lorson CL. A Direct Comparison of IV and ICV Delivery Methods for Gene Replacement Therapy in a Mouse Model of SMARD1. Mol Ther Methods Clin Dev. 2018 Aug 17;10:348-360. doi: 10.1016/j.omtm.2018.08.005. eCollection 2018 Sep 21.
- Villalón E, Shababi M, Kline R, Lorson ZC, Florea KM, Lorson CL. Selective vulnerability in neuronal populations in nmd/SMARD1 mice. Hum Mol Genet. 2018 Feb 15;27(4):679-690. doi: 10.1093/hmg/ddx434.
- Gray KM, Kaifer KA, Baillat D, Wen Y, Bonacci TR, Ebert AD, Raimer AC, Spring AM, Have ST, Glascock JJ, Gupta K, Van Duyne GD, Emanuele MJ, Lamond AI, Wagner EJ, Lorson CL, Matera AG. Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCFSlmb degron. Mol Biol Cell. 2018 Jan 15;29(2):96-110. doi: 10.1091/mbc.E17-11-0627. Epub 2017 Nov 22.
- Choi S, Calder AN, Miller EH, Anderson KP, Fiejtek DK, Rietz A, Li H, Cherry JJ, Quist KM, Xing X, Glicksman MA, Cuny GD, Lorson CL, Androphy EA, Hodgetts KJ. Optimization of a series of heterocycles as survival motor neuron gene transcription enhancers. Bioorg Med Chem Lett. 2017 Dec 1;27(23):5144-5148. doi: 10.1016/j.bmcl.2017.10.066. Epub 2017 Oct 26.
- Rindt H, Tom CM, Lorson CL, Mattis VB. Optimization of trans-Splicing for Huntington's Disease RNA Therapy. Front Neurosci. 2017 Oct 10;11:544. doi: 10.3389/fnins.2017.00544. eCollection 2017.
- Sison SL, Patitucci TN, Seminary ER, Villalon E, Lorson CL, Ebert AD. Astrocyte-produced miR-146a as a mediator of motor neuron loss in spinal muscular atrophy. Hum Mol Genet. 2017 Sep 1;26(17):3409-3420. doi: 10.1093/hmg/ddx230.
- Osman EY, Washington CW, Simon ME, Megiddo D, Greif H, Lorson CL. Analysis of Azithromycin Monohydrate as a Single or a Combinatorial Therapy in a Mouse Model of Severe Spinal Muscular Atrophy. J Neuromuscul Dis. 2017;4(3):237-249. doi: 10.3233/JND-170230.
- Rietz A, Li H, Quist KM, Cherry JJ, Lorson CL, Burnett BG, Kern NL, Calder AN, Fritsche M, Lusic H, Boaler PJ, Choi S, Xing X, Glicksman MA, Cuny GD, Androphy EJ, Hodgetts KJ. Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy. J Med Chem. 2017 Jun 8;60(11):4594-4610. doi: 10.1021/acs.jmedchem.6b01885. Epub 2017 May 19.
- Kline RA, Kaifer KA, Osman EY, Carella F, Tiberi A, Ross J, Pennetta G, Lorson CL, Murray LM. Comparison of independent screens on differentially vulnerable motor neurons reveals alpha-synuclein as a common modifier in motor neuron diseases. PLoS Genet. 2017 Mar 31;13(3):e1006680. doi: 10.1371/journal.pgen.1006680. eCollection 2017 Mar.
- Kaifer KA, Villalón E, Osman EY, Glascock JJ, Arnold LL, Cornelison DDW, Lorson CL. Plastin-3 extends survival and reduces severity in mouse models of spinal muscular atrophy. JCI Insight. 2017 Mar 9;2(5):e89970. doi: 10.1172/jci.insight.89970.
- SMN deficiency negatively impacts red pulp macrophages and spleen development in mouse models of spinal muscular atrophy. Khairallah MT, Astroski J, Custer SK, Androphy EJ, Franklin CL, Lorson CL. Hum Mol Genet. 2017 Mar 1;26(5):932-941. doi: 10.1093/hmg/ddx008.
- Osman EY, Washington CW 3rd, Kaifer KA, Mazzasette C, Patitucci TN, Florea KM, Simon ME, Ko CP, Ebert AD, Lorson CL. SMN deficiency negatively impacts red pulp macrophages and spleen development in mouse models of spinal muscular atrophy. Mol Ther. 2016 Sep;24(9):1592-601. doi: 10.1038/mt.2016.145. Epub 2016 Jul 9.
- Shababi M, Feng Z, Villalon E, Sibigtroth CM, Osman EY, Miller MR, Williams-Simon PA, Lombardi A, Sass TH, Atkinson AK, Garcia ML, Ko CP, Lorson CL. Rescue of a Mouse Model of Spinal Muscular Atrophy With Respiratory Distress Type 1 by AAV9-IGHMBP2 Is Dose Dependent. Mol Ther. 2016 May;24(5):855-66. doi: 10.1038/mt.2016.33. Epub 2016 Feb 10.
- Van Gronigen Caesar G, Dale JM, Osman EY, Garcia ML, Lorson CL, Schulz LC. Placental development in a mouse model of spinal muscular atrophy. Biochem Biophys Res Commun. 2016 Jan 29;470(1):82-87. doi: 10.1016/j.bbrc.2015.12.120. Epub 2015 Dec 31.
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