The main focus of the laboratory is the molecular understanding of genetic neuromuscular disorders. In particular, the laboratory focuses on unraveling the molecular biology of Spinal Muscular Atrophy (SMA). SMA is an autosomal recessive disorder that is characterized by destruction of motor neurons in the anterior horn of the spinal cord. The disorder can be classified according to clinical severity into three types. SMA is caused by loss or mutation of the SMN1 gene but not the virtually identical SMN2 gene. The two genes essentially differ by a single nucleotide that affects the incorporation of exon 7 into the SMN message. This results in the SMN2 gene producing insufficient SMN protein for motor neurons. SMN functions in the biogenesis of SnRNPs which is essential for all cells, currently it is not clear why high SMN levels are so critically important for motor neurons.

We have developed an animal model of SMA in the mouse and shown that high copy number of the SMN2 gene can rescue the SMA mouse. We are using this animal model of SMA to understand why motor neurons are affected and to develop treatments for SMA. A high throughput screen to identify compounds that can activate SMN has been started. It is hoped that these compounds can act as therapeutic reagents for SMA.

The laboratory is also developing gene therapy methods for treatment of Duchenne Muscular Dystrophy (DMD). DMD is a muscle wasting disorder caused by mutations in the large dystrophin gene. We are particularly interested in developing strategies that allow Adeno Associated Virus to be used for gene therapy of DMD.

Recent Publications:

• Le TT, McGovern VL, Alwine IE, Wang X, Massoni-Laporte A, Rich MM, Burghes AH (2011) "Temporal requirement for high SMN expression in SMA mice" Hum Mol Genet. Jun 13. [Epub ahead of print]

• Hao le T, Burghes AH and Beattie CE (2011) "Generation and Characterization of a genetic zebrafish model of SMA carrying the human SMN2 gene" Mol Neurodegener. 6(1):24.

• Burghes AH and McGovern VL (2010) "Antisense oligonucleotides and spinal muscular atrophy: skipping along" Genes Dev. 24(15):1574-9.

• Bevan AK, Hutchinson KR, Foust KD, Braun L, McGovern VL, Schmelzer L, Ward JG, Petruska JC, Lucchesi PA, Burghes AH and Kaspar BK (2010) "Early heart failure in the SMN{Delta}7 model of spinal muscular atrophy and correction by postnatal scAAV9-SMN delivery" Hum Mol Genet. 19(20):3895-905

• Ramesh T, Lyon AN, Pineda RH, Wang C, Janssen PM, Canan BD, Burghes AH and Beattie CE (2010) "A genetic model of amyotrophic lateral sclerosis in zebrafish displays phenotypic hallmarks of motoneuron disease" Dis Model Mech. 3(9-10):652-62.

• Foust KD, Wang X, McGovern VL, Braun L, Bevan AK, Haidet AM, Le TT, Morales PR, Rich MM, Burghes AH and Kaspar BK (2010) "Rescue of the spinal muscular atrophy phenotype in a mouse model by early postnatal delivery of SMN" Nat Biotechnol. 28(3):271-4.

• Butchbach ME, Singh J, Thornorsteinsdóttir M, Saieva L, Slominski E, Thurmond J, Andrésson T, Zhang J, Edwards JD, Simard LR, Pellizzoni L, Jarecki J, Burghes AH and Gurney ME (2009) "Effects of 2,4-diaminoquinazoline derivatives on SMN expression and phenotype in a mouse model for spinal muscular atrophy" Hum Mol Genet 19(3):454-67.

• Prior TW, Krainer AR, Hua Y, Swoboda KJ, Snyder PC, Bridgeman SJ, Burghes AH and Kissel JT (2009) "A positive modifier of spinal muscular atrophy in the SMN2 gene" Am J Hum Genet. 85(3):408-13.

• Burghes AH and Beattie CE (2009) "Spinal muscular atrophy: why do low levels of survival motor neuron protein make motor neurons sick?" Nat Rev Neurosci. 10(8):597-609.

• Workman E, Saieva L, Carrel TL, Crawford TO, Liu D, Lutz C, Beattie CE, Pellizzoni L and Burghes AH (2009) "A SMN missense mutation complements SMN2 restoring snRNPs and rescuing SMA mice" Hum Mol Genet. 18(12):2215-29.

• McGovern VL, Gavrilina TO, Beattie CE and Burghes AH (2008) "Embryonic motor axon development in the severe SMA mouse" Hum Mol Genet 17(18):2900-9.

• Burghes AH and Butchbach ME (2008) "Let all DNA vote: who are the amyotrophic lateral sclerosis candidates?" Neurology 70(9):662-3.

• Thurmond J, Butchbach ME, Palomo M, Pease B, Rao M, Bedell L, Keyvan M, Pai G, Mishra R, Haraldsson M, Andresson T, Bragason G, Thosteinsdottir M, Bjornsson JM, Coovert DD, Burghes AH, Burney ME and Singh J (2008) "Synthesis and biological evaluation of novel 2,4-diaminoquinazoline derivatives as SMN2 promoter activators for the potential treatment of spinal muscular atrophy" J Med Chem 51(3):449-69.

• Gavrilina TO, McGovern VL, Workman E, Crawford TO, Gogliotto RG, DiDonato CJ, Monani UR, Morris GE and Burghes AH (2008) "Neuronal SMN expression corrects spinal muscular atrophy in severe SMA mice while muscle-specific SMN expression has no phenotypic effect" Hum Mol Genet. 17(8):1063-75.

• McWhorter ML, Boon KL, Horan ES, Burghes AH and Beattie CE (2008) "The SMN binding protein Gemin2 is not involved in motor axon outgrowth" Dev Neurobiol. 68(2):182-94.

• Novoyatleva T, Heinrich B, Tang Y, Benderska N, Butchbach ME, Lorson CL, Lorson MA, Ben-Dov C, Fehlbaum P, Bracco L, Burghes AH, Bollen M and Stamm S (2007) "Protein phosphatase 1 binds to the RNA recognition motif of several splicing factors and regulates alternative pre-mRNA processing" Hum Mol Genet 17(1):52-70.

• Gabanella F, Butchbach ME, Saieva L, Carissimi C, Burghes AH and Pellizzoni L (2007) "Ribonucleoprotein Assembly Defects Correlate with Spinal Muscular Atrophy Severity and Preferentially Affect a Subset of Spliceosomal snRNPs" PLoS ONE 2(9):e921.

• Hao le T, Fuller HR, Lam le T, Le TT, Burghes AH and Morris GE (2007) "Absence of gemin5 from SMN complexes in nuclear Cajal bodies" BMC Cell Biol 8:28.

• Butchbach ME, Edwards JD and Burghes AH (2007) "Abnormal motor phenotype in the SMNDelta7 mouse model of spinal muscular atrophy" Neurobiol Dis. 27(2):207-19.

• Butchbach ME, Edwards JD, Schussler KR and Burghes AH (2006) "A novel method for oral delivery of drug compounds to the neonatal SMNDelta7 mouse model of spinal muscular atrophy" J Neurosci Methods 161(2):285-90.

• Carrel TL, McWhorter ML, Workman E, Zhang H, Wolstencroft EC, Lorson C, Bassell GJ, Burghes AHM and Beattie CE (2006) "Survival Motor Neuron Function in motor axons is independent of functions required for small nuclear ribunocleoprotein biogenesis" Neuroscience 26(43):11014-22.

• Acharyya S, Butchbach ME, Sahenk Z, Wang H, Saji M, Carathers M, Ringel MD, Skipworth RJ, Fearon KC, Hollingsworth MA, Muscarella P, Burghes AH, Rafael-Fortney JA and Guttridge DC (2005) "Dystrophin glycoprotein complex dysfunction: a regulatory link between muscular dystrophy and cancer cachexia" Cancer Cell 8(5):421-32.

• Bertini E, Burghes A, Bushby K, Estournet-Mathiaud B, Finkel RS, Hughes RA, Iannaccone ST, Melki J, Mercuri E, Muntoni F, Voit T, Reitter B, Swoboda KJ, Tiziano D, Tizzano E, Topaloglu H, Wirth B and Zerres K (2005) 134th ENMC International Workshop: Outcome Measures and Treatment of Spinal Muscular Atrophy, Naarden, The Netherlands. Neuromuscul Disord 15:802-16.

• Sharma A, Lambrechts A, Hao le T, Le TT, Sewry CA, Ampe C, Burghes AH and Morris GE (2005) "A role for complexes of survival of motor neurons (SMN) protein with gemins and profilin in neurite-like cytoplasmic extensions of cultured nerve cells" Exp Cell Res 309(1):185-97.

• Jarecki J, Chen X, Bernardino A, Coovert DD, Whitney M, Burghes A, Stack J and Pollok BA (2005) "Diverse small-molecule modulators of SMN expression found by high-throughput compound screening: early leads towards a therapeutic for spinal muscular atrophy" Hum Mol Genet 14(14):2003-18.

• Le TT, Pham LT, Butchbach ME, Zhang HL, Monani UR, Coovert DD, Gavrilina TO, Xing L, Bassell GL and Burghes AHM (2005) "SMN?7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN" Human Mol Genet 14(6):845-57.

• Mimoun A, Le T, Ralph GS, Walmsley L, Monani UR, Lee DCP, Wilkes F, Mitrophanous KA, Kingsman SM, Burghes AHM and Mazarakis ND (2004) "Lentivector-mediated SMN replacement in a mouse model of spinal muscular atrophy" J Clin Invest 114:1726.

• Butchbach M and Burghes A (2004) "Perspectives on models of spinal muscular atrophy for drug discovery" Drug Discov Today: Disease Models 2:151-6.

• Majumder S, Varadharaj S, Ghoshal K, Monani U, Burghes AH and Jacob ST (2004) "Identification of a novel cyclic AMP-response element (CRE-II) and the role of CREB-1 in the cAMP-induced expression of the survival motor neuron (SMN) gene" J Biol Chem 279(15):14803-11.

• Lunn MR, Root DE, Martino AM, Flaherty SP, Kelley BP, Coovert DD, Burghes AH, Nguyen TM, Morris GE, Zhou J, Androphy EJ, Sumner CJ and Stockwell BR (2004) "Indoprofen upregulates the survival motor neuron protein through a cyclooxygenase-independent mechanism" Chem Biol 11(11):1489-93.

• McWhorter ML, Monani UR, Burghes AH and Beattie CE (2003) "Knockdown of the survival motor neuron (Smn) protein in zebrafish causes defects in motor axon outgrowth and pathfinding" J Cell Biol 162(5):919-31.

• Sumner CJ, Huynh TN, Markowitz JA, Perhac JS, Hill B, Coovert D, Schussler K, Chen X, Jarecki J, Burghes AH, Taylor JP and Fischbeck KH (2003) "Valproic acid increases SMN levels in spinal muscular atrophy patient cells" Ann Neurol 54(5):647-54.

•  Monani UR, Pastore MT, Gavrilina TO, Jablonka S, Le TT, Andreassi C, DiCocco JM, Lorson C, Androphy EJ, Sendtner M, Podell M and Burghes AH (2003) "A transgene carrying an A2G missense mutation in the SMN gene modulate phenotypic severity in mice with severe (type 1) spinal muscular atrophy" J Cell Biol 160(1):41-52.