Cell Biology and Anatomy Discipline

Center for Genetic Diseases

Michelle Hastings, PhD, is a Professor and Director of the Center for Genetic Diseases at the Chicago Medical School at ÎÞÂëȺ½» of Medicine and Science. Her research focuses on understanding genetic basis of disease and discovering new therapeutics that modulate the process of pre-mRNA splicing to alter gene expression. Her work has resulted in the discovery of effective means of targeting splicing with antisense molecules for the potential treatment of a number of neurodegenerative diseases including Batten disease, Usher syndrome, cystic fibrosis, Alzheimer’s and Parkinson’s disease. Dr. Hastings’ studies on Usher syndrome led to the first demonstration that hearing and balance can be recovered in mice with a mutation that causes congenital deafness in humans, laying the groundwork for developing a treatment for Usher in humans. Her recent work has demonstrated that antisense technology can modulate gene expression pathways associated with Alzheimer’s disease to mitigate learning and memory deficits in mouse models of the disease. A major focus of the lab currently is on developing approaches to treat Batten disease using antisense technology. Dr. Hastings has many patents for her discoveries and has been supported by the National Institutes of Health and numerous Foundation grants. She is on the editorial board and scientific advisory boards for a number of journals and companies. She was recognized as a 2019 Researcher to Know by the Illinois Science and Technology Consortium.

Publications

• Moissoglu, K., Stueland, M., Gasparski, A.N., Wang, T., Jenkins, L.M., Hastings, M.L., and Mili, S. (2020) Local translation of RAB13 controls cell migration and GTPase function. EMBO J, 39: e104958. .
• Lentz, J.J., Pan, B., Ponnath, A., Tran, C.M., Nist-Lund, C., Galvin, A., Goldberg, H., Robillard, K.N., Jodelka, F.M., Farris, H.E., Huang, J., Zhu, H., Zhou, W., Rigo, F., Hastings, M.L., Geleoc, G.S.G. (2020) Direct delivery of antisense oligonucleotides to the middle and inner ear improves hearing and balance in Usher mice. Mol Ther, S1525-0016 (20)30412-3 .
• Korecka J.A., Thomas, R., Hinrich, A.J., Moskites, A.M., Macbain, Z.K., Hallett, P.J., Isacson, O., Hastings, M.L. (2020) Splice-switching antisense oligonucleotides reduce LRRK2 kinase activity in human LRRK2 transgenic mice. Mol Ther- Nucl. Acids, 21: 623-635. .
• Centa, J.L., Jodelka, F.M., Hinrich, A.J., Johnson, T.B., Ochaba, J., Norrbom, M., Weimer, J.M., Rigo, F., Duelli, D.M., Hastings, M.L. (2020) Therapeutic efficacy of antisense oligonucleotides in mouse models of CLN3 Batten disease. Nature Med. Doi: 10.1038/s14591-020-0986-1. .
• Michaels, W.E., Bridges, R.J., Hastings, M.L. (2020) Antisense oligonucleotide-mediated correction of CFTR 3849+10kbC>T splicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells. Nucleic Acids Res. 48: 7454-7467
• Wang, L., Kempton, J.B., Jiang, H., Jodelka, F.M., Brigande, A.M., Dumont, R.A., Rigo, F., Lentz, J.J., Hastings, M.L., Brigande, J.V. (2020) Fetal antisense therapy for congenital deafness and balance dysfunction. Nucleic Acids Res. Doi:10.1093/nar/gkaa194. PMID: 32249312
• Korecka J.A., Thomas R., Christensen D.P., Hinrich A.J., Ferrari E.J., Levy S.A., Hastings M.L., Hallett P.J., Isacson O. (2019). Mitochondrial clearance and maturation of autophagosomes are compromised in LRRK2 G2019S familial Parkinson's disease patient fibroblasts. PMID:
• Hastings, M.L., Brigande, J.B. (2020) Fetal gene therapy and pharmacotherapy to treat congenital hearing loss and vestibular dysfunction. Hearing Res. Doi:10.1016/j.heares.2020.107931. .
• Hastings M.L. and Jones, T.A. (2019) Antisense Oligonucleotides for the Treatment of Inner Ear Dysfunction. PMID: 30972560 PMCID:
• Korecka J.A., Talbot S., Osborn T.M., de Leeuw S.M., Levy S.A., Ferrari E.J., Moskites A., Jodelka F.M., Hinrich A.J., Hastings M.L., Woolf C.H., Hallett P.J. Osacson O. (2019) Neurite Collapse and Altered ER Ca2+ Control in Human Parkinson Disease Patient iPSC-Derived Neurons with LRRK2 G2019S Mutation. PMID: 30595548 . PMCID:
• Timm D., Cain J.T., Geraets R.D., White K.A., Koh S.Y., Kielian T., Pearce D.A., Hastings M.L., Weimer J.M. (2018) Searching for novel biomarkers using a mouse model of CLN3-Batten disease. PMID 30086172 . PMCID: .
• Parnell S.C., Magenheimer B.S., Maser R.L., Pavlov T.S., Havens M.A., Hastings M.L., Jackson S.F., Ward C.J., Peterson K.R., Staruschenko A., Calvet J.P. (2018) A Mutation Affecting Polycystin-1 Mediated Heterotrimeric G-Protein Signaling Causes PKD. Hum Mol Genet. 2018 Jun 20. [Epub ahead of print].
• Chang J.L., Hinrich A.J., Roman B., Norrbom M., Rigo F., Marr R.A., Norstrom E.M., Hastings M.L. (2018) Targeting Amyloid-β Precursor Protein, APP, Splicing with Antisense Oligonucleotides Reduces Toxic Amyloid-β Production. Mol Ther. 26:1539-1551.
• Ponnath A., Depreux F.F., Jodelka F.M., Rigo F., Farris H.E., Hastings M.L., Lentz J.J. (2018) Rescue of Outer Hair Cells with Antisense Oligonucleotides in Usher Mice Is Dependent on Age of Treatment. J Assoc Res Otolaryngol. 19:1-16.
• Donaldson T.N., Jennings K.T., Cherep L.A., McNeela A.M., Depreux F.F., Jodelka F.M., Hastings M.L., Wallace D.G. (2018) Antisense oligonucleotide therapy rescues disruptions in organization of exploratory movements associated with Usher syndrome type 1C in mice. Behav Brain Res. 338:76-87.
• Vijayakumar, S., Depreux, F., Jodelka, F.M., Lentz, J.J., Rigo, F., Jones, T.A., Hastings, M.L. (2017) Rescue of peripheral vestibular function in Usher syndrome mice using a splice-switching antisense oligonucleotide. Hum. Mol. Genet. 1093/hmg/ddx234.
• Pan, B., Askew, C., Galvin, A., Heman-Ackah, S., Asai, Y., Indzhykulian, A.A., Jodelka, F.M., Hastings, M.L., Lentz, J.J., Vandenberghe, L.H., Holt, J.R., and Geleoc, G.G.S. (2017) Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome, type IC. Nature Biotech. Feb. 6; nbt.3801.
• Donovan, R., Kelly, S., Prazad, P., Talaty, P.N., Lefaiver, C., Hastings, M.L., Everly, D.N. (2016) The Effects of Human Milk Fortification on Nutrients and Milk Properties. J. Perinatol., 37: 42-48.
• Depreux, F.F, Wang L., Jiang, H., Jodelka, F.M., Rosencrans R.F., Rigo, F., Lentz, J.J., Brigande, J.V., and Hastings, M.L. (2016) Antisense oligonucleotides delivered to the amniotic cavity in utero modulate gene expression in the postnatal mouse. Nucleic Acids Res. 44: 9519-9529. *Selected Breakthrough article. *Featured on WBEZ Chicago radio: “Chicago Researchers Make Significant Finding in Treating Genetic Defects In Utero.
• Havens, M.A., and Hastings, M.L. (2016) Splice-switching antisense oligonucleotides as therapeutic drugs. Nucleic Acids Res. 44: 5549-5563.
• Geraets, R.D., Koh, S.Y., Hastings, M.L., Kielian, T., Pearce, D.A., and Weimer, J.M. (2016) Moving Towards effective therapeutic strategies for neuronal ceroid lipofuscinosis. Orphanet J Rare Dis. 11, 40-53.
• Hinrich, A.J., Jodelka, F.M., Chang, J.L., Brutman, D., Bruno, A.M., Briggs, C.A., James, B.D., Stutzmann, G.E., Bennett, D.A., Miller, S.A., Rigo, F., Marr, R.A., and Hastings, M.L. (2016) Therapeutic correction of ApoER2 splicing in Alzheimer’s disease mice using antisense oligonucleotides. EMBO Mol. Med. 8: 328-345. ). *News and Views: Wasser, C.R. & Herz J. (2016) Splicing therapeutics for Alzheimer’s disease. EMBO Mol. Med. 8: 308-310 (PMID: 26902203).
• Hastings, M.L. (2015) A big score for RNA. RNA. 21: 634-635.
• Case, A.M., Sawyer, I.A., Dundr, M., and Hastings, M.L. (2015) Pre-mRNA splicing: function and dysfunction. Encyclopedia of Cell Biology, Volume 1: Molecular Cell Biology edited by Ralph A Bradshaw and Philip D Stahl, 01/2016: chapter Pre-mRNA Splicing: Function and Dysfunction: pages 503-511; Elsevier, ISBN: 978-0-12-394796-3.
• Wee, C.D., Havens, M.A., Jodelka, F.M., Hastings, M.L. (2014) Targeting SR Proteins Improves SMN Expression in Spinal Muscular Atrophy Cells. PLoS ONE, 9: e115205.
• Havens, M.A., Reich, A.A., Hastings, M.L. Drosha Promotes Splicing of a Pre-microRNA-like Alternative Exon. PLoS Genetics, 10: e1004312.
• Dauber, A., Golzio C., Guenot, C., Jodelka, F.M., Kibaek, M., Kjaergaard, S., Leheup, B., Martinet, D., Nowaczyk, M., Rosenfeld, J.A., Zeesman, S., Zunich, J., Beckmann, J.S., Hirschhorn, J.N., Hastings, M.L.*, Jacquemont, S.*, Katsanis, N.* SCRIB and PUF60 are primary drivers of the multisystemic phenotypes of the 8q23.4 copy number variant. Am. J. Hum. Genet. 93: 798-811. *co-senior authors.
• Allemand, E., and Hastings, M.L. (2014) Expression and Purification of Splicing Proteins. Methods Mol. Biol. 1126: 205-216.
• Lentz, J.J., Jodelka, F.M., Hinrich, A.J., McCaffrey, K.E., Farris, H.E., Spalitta, M.J., Bazan, N.G., Duelli, D.M., Rigo, F., Hastings, M.L. (2013) Correction of hearing and vestibular dysfunction in a mouse model of deafness. Nature Med, 19: 345-350.
• Quarles, K.A., Sahu, D., Havens, M.A., Forsyth, E.R., Wostenberg, C., Hastings, M.L., and Showalter, S.A. Ensemble analysis of primary miRNA structure reveals an extensive capacity to deform near the Drosha cleavage site. Biochemistry, 52: 795-807.
• Havens, M.A., Duelli, D.M. and Hastings, M.L. (2013) Targeting RNA splicing for disease therapy. Wiley Interdiscip Rev RNA, 4: 247-266.
• Duelli, D.M., Palma, J., Beaman, K., Hastings, M.L., Kwak-Kim, J. Linnstaedt, S., Park, J.C., and Kim, D.J. (2013) MicroRNA detection in plasma samples: How to treat heparinized plasma. J. Mol. Diagn. 15: 138-139. *Author’s reply.
• Hastings, M.L., Palma, J., and Duelli, D.M. (2012) Sensitive PCR-based quantitation of circulating cell-free microRNAs. Methods 58: 144-150.
• Palma, J., Yaddanapudi, S.C., Pigati, L., Havens, M.A., Jeong, S., Weimer, K., Stern, B., Hastings, M.L., and Duelli, D.M. (2012) MicroRNAs are exported from malignant cells in customized particles. Nucleic Acids Res, 40: 9125-9138.
• Havens, M.A., Reich, A.A., Duelli, D.M., and Hastings, M.L. (2012) Biogenesis of mammalian microRNAs by a non-canonical processing pathway. Nucleic Acids Res, 40: 4626-4640. *Featured article.
• Kim, D.J., Linnstaedt, S., Palma, J., Park, J.C., Ntrivalas, E., Kwak-Kim, J.Y.H., Gilman-Sachs, A., Beaman, K., Hastings, M.L., Martin, J.N., and Duelli, D.M. (2012) Plasma components affect accuracy of circulating cancer-related microRNA quantitation. J. Mol. Diagn. 14: 71-80. *Faculty of 1000 article.
• Bruno, A., Huang, J, Bennett, D.A., Marr, R., Hastings, M.L., and Stutzmann, G.E. (2012) Altered ryanodine receptor expression in mild cognitive impairment and Alzheimer’s disease. Neurobiol. Aging, 33: 1001.e1-6.
• Vorlova, S., Rocco, G., LeFave, C.V., Jodelka, F.M., Hastings, M.L., Henke, E., and Cartegni, L. (2011) Induction of antagonistic soluble decoy receptor tyrosine kinases by intronic polyA activation. Mol. Cell, 43: 927-939.
• Jodelka, F.M., Ebert, A.D., Duelli, D.M., and Hastings, M.L. (2010) A feedback loop regulates splicing of the spinal muscular atrophy-modifying gene, SMN2. Hum. Mol. Genet. 19: 4906-17.
• Pigati, L., Yaddanapudi, S., Iyengar, R., Kim, D.J., Hearn, S., Danforth, D., Hastings M.L., Duelli, D.M. (2010) Selective Release of MicroRNA Species from Normal and Malignant Mammary Epithelial Cells. PLoS One. .
• Salato, V.K., Rediske, N.W., Zhang, C., Hastings, M.L., and Munroe, S. H. (2010) An exonic splicing enhancer within a bidirectional coding sequence regulates splicing of thyroid hormone receptor mRNA. RNA Biology, 7: 179-90.
• Hastings, M.L., Berniac, J., Liu, Y.H., Abato, P., Jodelka, F.M., Barthel, L., Kumar, S., Dudley, C., Larson, K., Edmonds, J., Bowser, T., Draper, M., Higgins, P., and Krainer, A.R. (2009) Tetracyclines that promote SMN2 exon 7 splicing as therapeutics for spinal muscular atrophy. Sci. Transl. Med. 1: 5ra12. PMID: 20161659.
• Martins de Araujo, M., Bonnal, S., Hastings, M.L., Krainer, A.R. and Valcarcel, J. (2009) Differential 3’ splice site recognition of SMN1 and SMN2 transcripts by U2AF and U2 snRNP. RNA 15: 515-523.
• Hastings, M.L. and Sachidanandam, R. (2008) Evolutionary conservation of splice sites. In: Encyclopedia of Life Sciences (ELS). John Wiley & Sons, Ltd: Chichester. DOI: 10.1002/9780470015902.a0020782.
• Zhang, C., Hastings, M.L., Krainer, A.R. and Zhang, M.Q. (2007) Dual-specificity splice sites are used as both 5’ and 3’ splice sites. Proc. Natl. Acad. Sci. USA 104: 15028-15033.
• Hastings, M.L., Allemand, E., Duelli, D.M., Myers, M.P. and Krainer, A.R. (2007) Control of pre-mRNA splicing by the general splicing factors PUF60 and U2AF65. PLoS ONE 2: e538.
• Allemand, E., Hastings, M.L., Murray, M.V., Myers, M.P. and Krainer, A.R. (2007) Alternative splicing regulation by interaction of phosphatase PP2Cg and nucleic acid-binding protein YB-1. Nature Struct. Mol. Biol. 14: 630-638. PMID: 17572683.
• Sheth, N., Roca, X., Hastings, M.L., Roeder, T., Krainer, A.R. and Sachidanandam, R. (2006) Comprehensive splice-site analysis using comparative genomics. Nucleic Acids Res. 34: 3955-3967. PMID: 16914448.
• Cartegni, L.*, Hastings, M.L.*, Calarco, J.A., de Stanchina, E. and Krainer, A.R. (2006) Determinants of exon 7 identity in the spinal muscular atrophy genes, SMN1 and SMN2. Am. J. Hum. Genet. 78: 63-77. *equal contributors
• Hastings, M.L., Resta, N., Traum, D., Stella, A., Guanti, G. and Krainer, A.R. (2005). An LKB1 AT-AC intron causes Peutz-Jeghers syndrome via splicing at non-canonical cryptic splice sites. Nature Struct. Mol. Biol. 12 : 54-59.
• Hastings, M.L. and Krainer, A.R. (2001). Pre-mRNA splicing in the new millennium. Curr. Opin. Cell Biol. 13: 302-309.
• Hastings, M.L. and Krainer, A.R. (2001). Functions of SR proteins in the U12-dependent AT-AC pre-mRNA splicing pathway. RNA 7: 471-482.
• Hastings, M.L., Wilson, C.M. and Munroe, S.H. (2001). A purine-rich intronic element enhances alternative splicing of thyroid hormone receptor mRNA. RNA 7:859-874.
• Hastings, M.L., Ingle, H.A., Lazar, M.A. and Munroe, S.H. (2000). Post-transcriptional regulation of thyroid hormone receptor expression by cis-acting sequences and a naturally occurring antisense RNA. J. Biol. Chem. 275:11507-11513.
• Hastings, M.L., Milcarek, C., Martincic, K., Peterson, M.L. and Munroe, S.H. (1997). Expression of the thyroid hormone receptor gene, erbAa, in B lymphocytes: alternative mRNA processing is independent of differentiation but correlates with antisense RNA levels. Nucleic Acids Res. 25: 4296-4300.