Professor of Veterinary Pathobiology
Fields of Interest
- Molecular Genetics
- Gene Therapy
- Ph.D. 1997, University of Missouri-Columbia
- B.A. 1991, Colorado College
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.
SMA is an extremely intriguing target for therapeutic intervention for a number of reasons: 1) While SMA presents in a broad clinical spectrum, a single gene is responsible for all clinical forms of the disease (severe; intermediate; mild); 2) Loss of SMN1andSMN2 is lethal, therefore essentially all SMA patients typically retain one or more copies of SMN2; 3) SMN2encodes a fully functional SMN protein. Therefore, by identifying molecules that stimulate full-length SMN expression from the SMN2 gene, these molecules could lead to the development of effective therapies for a broad range of SMA patient populations.
Several ongoing projects in the lab include:
Bi-functional RNAs delivered via a gene therapy vector
To take advantage of the unique SMA genetic context, we are developing short RNAs that modulate SMN2 pre-mRNA splicing. Bi-functional RNAs derive their name due to the presence of two distinct domains: an RNA sequence that is complimentary to a specific cellular RNA (e.g. SMN); and an untethered RNA segment that serves as a sequence-specific binding platform for cellular splicing factors, such as SR and SR-like proteins. A large number of RNAs have been screened in cellular assays. From this work, a subset of lead candidate RNAs has been identified and will further delineate the most efficient RNAs that modulate SMN2 splicing patterns. The top candidate RNAs will then be expressed via a viral vector with and without the co-expression of a neurotrophic factors in a murine model of SMA. These experiments will determine whether a post-natal increase of SMN is sufficient or whether a soluble neurotrophic factor can aid in motor neuron survival. These experiments will also determine whether the RNAs can modulate SMN2 in an organism and whether this expected increase in full-length SMN2 expression lessens the SMA phenotype in transgenic mice.
Trans-splicing delivered via a gene therapy vector
Recently a therapeutic approach has been developed referred to as trans-splicing. Conceptually, this strategy relies upon pre-mRNA splicing occurring between two separate molecules: 1) the endogenous target RNA and 2) the therapeutic RNA that provides the correct RNA sequence via a trans-splicing event. SMN trans-splicing RNAs were initially examined and expressed from a plasmid-backbone and shown to re-direct splicing from a SMN2 mini-gene as well as from endogenous transcripts. Subsequently, recombinant adeno-associated viral vectors were developed that expressed and delivered trans-splicing RNAs to SMA patient fibroblasts. In the severe SMA patient fibroblasts, SMN2 splicing was redirected via trans-splicing to produce increased levels of full-length SMN mRNA and total SMN protein levels. Finally, snRNP assembly, a critical function of SMN, was restored to SMN-deficient SMA fibroblasts following treatment with the trans-splicing vector. Together these results demonstrate that the alternatively spliced SMN2 exon 7 is a tractable target for replacement by trans-splicing.
Previously, we have shown that for some functions, heterologous sequences can compensate for the exon 7 peptide, suggesting that the SMN C-terminus functions non-specifically. Consistent with this hypothesis, we have identified novel aminoglycosides that can induce SMN protein levels in patient fibroblasts. This hypothesis was supported, in part, by a novel fluorescent SMN read-through assay. Interestingly, however, through the development of a SMN exon 7-specific antibody, results suggested that levels of normal full-length SMN may also be elevated by aminoglycoside treatment. These results demonstrate that compounds that promote read-through may provide an alternative platform for the discovery of compounds that induce SMN protein levels.
- Rindt H, Z. Feng, C. Mazzasette, J.J. Glascock, D. Valdivia, N. Pyles, T.O. Crawford, K.J., Swoboda, T.N. Patitucci, A.D. Ebert, C.J. Sumner, C.P. Ko, and C.L. Lorson. 2015. Astrocytes influence the severity of spinal muscular atrophy. Hum Mol Genet. 2015 Jul 15;24(14):4094-102. doi: 10.1093/hmg/ddv148. Epub 2015 Apr 24.
- Seng, C.O., C. Magee, P.J. Young, C.L. Lorson and J.P. Allen. 2015. The SMN structure reveals its crucial role in snRNP assembly. Hum Mol Genet. 2015 Apr 15;24(8):2138-46. doi: 10.1093/hmg/ddu734. Epub 2015 Jan 5.
- Osman E.Y., M.R. Miller, K.L. Robbins, A.M. Lombardi, A.K. Atkinson, A.J. Brehm, and C.L. Lorson. Morpholino antisense oligonucleotides targeting intronic repressor Element1 improve phenotype in SMA mouse models. Hum Mol Genet. 2014 Apr 29. pii: ddu198. [Epub ahead of print]
- Robbins, K.L., J.J. Glascock, E.Y. Osman, M.R. Miller, and C.L. Lorson. Defining the therapeutic window in a severe animal model of Spinal Muscular Atrophy. Hum Mol Genet. 2014 Apr 9. [Epub ahead of print]
- Shababi, M., C.L. Lorson, and S.S. Rudnik-Schöneborn. 2013. Spinal muscular atrophy: a motor neuron disorder or a multi-organ disease? J Anat. 2013 Jul 22. doi: 10.1111/joa.12083 [Epub ahead of print]
- Cherry, J.J., E.Y. Osman, M.C. Evans, S. Choi, X. Xing, G.D. Cury, M.A. Glicksman, C.L. Lorson, and E.J. Androphy. 2013. Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug-like compounds. EMBO Mol Med. 2013 Jul;5(7):1103-18. doi: 10.1002/emmm.201202305. Epub 2013 Jun 5
- Taylor AS, J.J. Glascock, F.F. Rose Jr, C. Lutz, C.L. Lorson. 2013. Restoration of SMN to Emx-1 expressing cortical neurons is not sufficient to provide benefit to a severe mouse model of Spinal Muscular Atrophy. Transgenic Res. 2013 Mar 20. [Epub ahead of print]
- Cobb MS, F.F. Rose, H. Rindt, J.J. Glascock, M. Shababi, M.R. Miller, E.Y. Osman, P.F. Yen, M.L. Garcia, B.R. Martin, M.J. Wetz, C. Mazzasette, Z. Feng, C.P. Ko, C.L. Lorson. 2013. Development and characterization of an SMN2-based intermediate mouse model of Spinal Muscular Atrophy. Hum Mol Genet. 2013 May 1;22(9):1843-55. doi: 10.1093/hmg/ddt037. Epub 2013 Feb 5.
- Lorson, M.A. and C.L. Lorson. 2012. SMN-inducing compounds for the treatment of spinal muscular atrophy. Future Med Chem. Oct; 4(16):2067-84. doi: 10.4155/fmc.12.131.
- Mattis VB, C.W. Chang, C.L. Lorson. 2012. Analysis of a read-through promoting compound in a severe mouse model of spinal muscular atrophy. 2012. Neurosci Lett. 525(1):72-75. Epub. July 20.
- Rindt H, P.F. Yen, C.N. Thebeau, T.S. Peterson, G.A. Weisman, C.L. Lorson. Replacement of huntingtin exon 1 by trans-splicing. 2012. Cell Mol Life Sci. Epub. July 20.
- Shababi, M., J. Hababi, L. Ma, J.J. Glascock, J.R. Sowers, C.L. Lorson. 2012. Partial restoration of cardio-vascular defects in a rescued severe model of Spinal Muscular Atrophy. J. Mol Cell Cardiol. 52(5):1074-82. Epub 2012 Jan. 17.
- Glascock JJ, Shababi M, Wetz MJ, Krogman MM, Lorson CL. 2012. Direct central nervous system delivery provides enhanced protection following vector mediated gene replacement in a severe model of Spinal Muscular Atrophy. Biochem Biophys Res Commun. 417(1):376-81. Epub Dec. 8, 2011.
- Rindt, H., D.M. Buckley, S.M. Vale, M. Krogman, F.F. Rose Jr., M.L. Garcia, C.L. Lorson. 2012. Transgenic inactivation of murine myostatin does not decrease the severity of disease in a model of Spinal Muscular Atrophy. Neuromuscul. Disord. 22(3):277-85. Epub Nov. 10, 2011.
- Glascock, J, E.Y. Osman, M.J. Wetz, M.M. Krogman, M. Shababi, C. Lorson. 2012. Decreasing disease severity in symptomatic Spinal Muscular Atrophy mice following scAAV9-SMN delivery. Hum Gene Ther. Epub Oct 26, 2011.
- Osman, E.Y., P.F. Yen, C.L. Lorson. 2011. Bifunctional RNAs targeting the intronic splicing silencer N1 increase SMN levels and reduce disease severity in an animal model of spinal muscular atrophy. Mol Therapy. 20(1):119-26. Epub Oct 25, 2011.
- Lorson, M.A., L.D. Spate, M.S. Samuel, C.N. Murphy, C.L. Lorson, R.S. Prather, and K.D. Wells. 2011. Disruption of the Survival Motor Neuron (SMN) Gene in Pigs Using ssDNA. Transgenic Res. Epub Feb 17, 2011.
- Dale, J.M., H. Shen, D.M. Barry, V.B. Garcia, F.F. Rose, C.L. Lorson, M.L. Garcia. 2011. The spinal muscular atrophy mouse model, SMAÎ”7, displays altered axonal transport without global neurofilament alterations. Acta Neuropathol. Epub: June 17, 2011.
- Glascock, J.J., E. Osman, T.H. Coady, F.F. Rose, M. Shababi, C.L. Lorson. 2011. Delivery of therapeutic agents through intracerebroventricular (ICV) and intravenous (IV) injection in mice. J Vis Exp. Oct 3;(56). pii: 2968. doi: 10.3791/2968.
- Shababi, M., C.L. Lorson. 2011. Optimization of SMN Trans-Splicing Through the Analysis of SMN Introns. J Mol Neurosci. Epub Aug 9, 2011.
- Jayakumar, C., M. Evans, V. Thayanithy, N. Taniguchi-Ishigaki, I. Bach, A. Kolpak, G. Bassell, W. Rossoll, C.L. Lorson, Z.Z. Bao, E.J. Androphy. 2011. The COP1 vesicle complex binds and moves with Survival Motor Neuron within axons. Hum. Mol. Genet. 20(9):1701-11.
- Coady, T.H., C.L. Lorson. 2011. SMN in SMA and snRNP biogenesis. Wiley WIRES RNA. RNA in Disease Development. Review. 2:546-564.
- Shababi, M., J. Glascock, C.L. Lorson. 2010. Combination of SMN Trans-Splicing and a Neurotrophic Factor Increases the Life Span and Body Mass in a Severe Model of Spinal Muscular Atrophy. Hum Gene Ther. Epub Dec 12, 2010.
- Shababi, M., V.B. Mattis, C.L. Lorson. 2010. Therapeutics that directly increase SMN expression to treat spinal muscular atrophy. Oct;23(8):475-82. Drug News Perspect.
- Shababi, M., J. Hababi, H.T. Yang, S.M. Vale, W.A. Sewell, C.L. Lorson. 2010. Cardiac defects contribute to the pathology of spinal muscular atrophy models. Hum Mol Gen. 19(20):4059-71.
- Lorson, C.L., H. Rindt, M. Shababi. Spinal Muscular Atrophy: mechanisms and therapeutic strategies. 2010. Hum Mol Genet. 2010 Apr 15;19(R1):R111-8.
- Shaw, D.J., R. Morse, A.G. Todd, P. Eggleton, C.L. Lorson, P.J. Young. 2010. Identification of a self-association domain in the Ewing’s sarcoma protein: a novel function for arginine-glycine-glycine rich motifs? J of Biochem 2010 Jun;147(6):885-93.
- Coady, T.H. and C.L. Lorson. 2010. Trans-splicing-mediated improvement in a severe mouse model of spinal muscular atrophy. J. Neuroscience 6;30(1):126-30.
- Butchbach, M.E., F.F. Rose Jr, S. Rhoades, J. Marston, J.T. McCrone, R. Sinnott, C.L. Lorson. 2010. Effect of diet on the survival and phenotype of a mouse model for spinal muscular atrophy.Biochem Biophys Res Commun. 91(1):835-40.
- Mattis, V.B., M.Y. Fosso, C.W. Chang, C.L. Lorson. 2009. Subcutaneous administration of TC007 reduces disease severity in an animal model of SMA. BMC Neurosci. 2009 Oct 15;18(20):3906-13.
- Shaw, D.J., R. Morse, A.G. Todd, C.L. Lorson, P. Eggleton and P.J. Young. 2009. Identification of a tripartite import signal in the Ewing Sarcoma protein (EWS). 390(4):1197-201. Biochem Biophys Res Commun.
- Mattis, V., A.D. Ebert, M.Y. Fosso, C.-W. Chang, C.L. Lorson. 2009. Delivery of a read-through inducing compound, TC007, lessens the severity of a SMA animal model. Hum Mol Gen (20):3906-13. Epub 2009 Jul 21.
- Le Roy, F., K. Charton, C.L. Lorson, I. Richard. 2009. Shooting the messenger: RNA-targeting approaches for muscle diseases. (REVIEW) Trends in Mol Med (12):580-91.
- Baughan, T.D., A. Dickson, E.Y. Osman, C.L. Lorson. 2009. Delivery of bifunctional RNAs that target an intronic repressor and increase SMN levels in an animal model of spinal muscular atrophy. Hum Mol Genet. 18(9):1600-11. Epub 2009 Feb 19.
- Rose, F.F., V.B. Mattis, H. Rindt, C.L. Lorson. 2009. Delivery of recombinant follistatin lessens the severity of disease in a mouse model of spinal muscular atrophy. Hum Mol Genet 18(6):997-1005. Epub 2008 Dec 12.
- Evert, A.D., Rose, F.F., V.B. Mattis, C.L. Lorson, J.A. Thomson, C.N. Svendsen. 2009. Generation and differentiation of induced pluripotent stem cells from a spinal muscular atrophy patient. Nature. 457(7227):277-80. Epub 2008 Dec 21.
- Coady, T.H., M. Shababi, T.D. Baughan, M.A. Passini, C.L. Lorson. Development of a single vector system that enhances trans-splicing of SMN2 transcripts. PLoS ONE. 2008; 3(10):e3468. Epub 2008 Oct. 22.
- Dickson, A., E. Osman, C.L. Lorson. A Negatively-Acting Bifunctional RNA Increases Survival Motor Neuron in vitro and in vivo. Human Gene Therapy. 200819(11): 1307-1316. Epub ahead of print Aug. 25.
- Mattis, V.B., M.E.R. Butchbach, C.L. Lorson. Detection of human survival motor neuron (SMN) protein in mice containing the SMN2 transgene: applicability to preclinical therapy development for spinal muscular atrophy. J Neurosci Methods. Oct 30; 175(1):36-43. Epub 2008 Aug 15.
- Lorson, M.A., A.M. Dickson, D.J. Shaw, A.G. Todd, E.C. Young, R. Morse, C. Wolstencroft, C.L. Lorson, and P.J. Young. Identification and Characterisation of a Nuclear Localisation Signal in the SMN associated protein, Gemin4. Biochem Biophys Res Commun. Oct 10, 375(1):33-7. Epub 2008 Jul 31.
- Rose, F.F., P. Meehan, T.H. Coady, V.B. Garcia, M. Garcia, C.L. Lorson. The Wallerian degeneration slow (Wlds) gene does not attenuate disease in a mouse model of spinal muscular atrophy. In Press. Biochem Biophys Res Commun.
- Mattis, V.B., M. Bowman, R. Kothary, C.L. Lorson. 2008. A SMNÎ”7 read-through product confers funtionality to the SMNÎ”7 protein. Neuroscience Letters. Sep 5; 442(1):54-8. Epub 2008 Jun 26.
- Lorson, M.A., L.D. Spate, R.S. Prather and C.L. Lorson. 2008. The identification and characterization of the porcine (Sus scrofa) Survival Motor Neuron (SMN1) gene: An animal model for therapeutic studies. Devel. Dynamics. Aug; 237(8):2268-78.
- T. Novoyatleva, B. Heinrich, Y. Tang, N. Benderska, C. Ben-Dov, P. Fehlbaum, L. Bracco, M.E.R. Butchbach, A. Burghes, M.L. Lorson, C.L. Lorson, M. Bollen and S. Stamm. 2008. Protein phosphatase 1 binds to the RNA recognition motif of several splicing factors and regulates alternative pre-mRNA processing. Hum. Mol. Genetic. 17(1):52-70.
- Sakla, M.S., C. L. Lorson. 2008. Induction of full-length Survival Motor Neuron (SMN) by polyphenol botanical compounds. Human Genet.122(6):635-43.