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Ravindra N Singh

PhD
Ravindra N Singh

Professor
Biomedical Sciences
singhr@iastate.edu
515-294-8505
2034 Patterson
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Education & Certifications

  • PhD, Biochemistry, 1993, Institute of Biochemistry and Physiology of Microorganisms, Russian Academy of Sciences, Pushchino, Russia
  • MSc, Biochemistry, 1985, Banaras Hindu University, Varanasi, India
  • BSc, Chemistry Honors, 1983, Banaras Hindu University, Varanasi, India

Teaching

  • Present                               BMS 575, Cellular and Molecular Biology

Research Focus & Interests

Research in Singh laboratory focuses on molecular mechanism(s) of spinal muscular atrophy (SMA) that results from the loss of Survival of Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, cannot compensate for the loss of SMN1 due to skipping of SMN2 exon 7. The presence of SMN2 makes SMA a unique disease in which almost all patients carry a gene (SMN2) with potential to be corrected. Singh lab discovered Intronic Splicing Silencer N1 (ISS-N1) target that led to the clinical development of nusinersen (SpinrazaTM), an antisense oligonucleotide (ASO), which was approved by FDA (USA) in 2016 as the first drug for the treatment of SMA. ISS-N1-targeting ASOs (abbreviated as “N1ASOs”) remain the most studied ASOs in the context of a human disease. In addition to the seminal discovery of ISS-N1, Singh lab identified and characterized a GC-rich sequence as the shortest target for an ASO-mediated splicing correction in SMA. Further research uncovered that blocking of this target by an 8-mer ASO confers therapeutic benefit in both severe and mild models in SMA. Singh lab developed a powerful multi-exon-skipping detection assay (MESDA) that reveals the relative abundance of SMN transcripts in a single reaction. Singh lab credited with probing the entire structure of SMN2 intron 7 and demonstrating that an ASO-mediated sequestration of the deep intronic target, ISS-N2, leads to gender-specific amelioration of a mild mouse model of SMA. These results confirmed for the first time the therapeutic potential of an RNA structure formed by an intra-intronic long-distance interaction. Further, Singh lab confirmed the proof of principle of a novel treatment strategy, based on the activation of a cryptic 5¢ splice site employing an engineered U1 snRNA (eU1), as an alternative for SMA patients who may not benefit from SpinrazaTM due to absence of a function 5¢ss of SMN1/2 exon 7. In addition, Singh lab demonstrated that RNA-SMN interactions are governed by unique sequence and structural preferences. Research in Singh lab has discovered a vast repertoire of circular RNAs (circRNAs) of SMN1/2, including those encompassing novel exons generated by intergenic or downstream-of-gene (DoG) transcription. His lab also uncovered functions of circRNAs encompassing four early exons of SMN1/2. Recently, Singh lab has shown how off-target effects of a therapeutic ASO could be minimized employing a combination of strategies. 

News Links about Dr. Ravindra Singh:

Honors & Awards

  • 2006 Presidential Early Career Award for Scientists and Engineers  (PECASE award: this is the highest civilian award of US Government to promising young scientists)
  • Salsbury Endowed Chair in Veterinary Medicine, Iowa State University
  • USSR/India Scientific Exchange Fellowship

Leadership/Committees/Council

Organizer for symposia

2019: Organizing committee member: Corn-belt RNA meeting (October 18-19, 2019; Columbia, Missouri, USA)

2014: Co-chair and organizing committee member: 2nd CVM Research Symposium (January 8, 2014; Ames, IA)

2013: Co-chair and organizing committee member: 1st CVM Research Symposium (January 8, 2013; Ames, IA)

2010: Organizing committee member and session co-chair: One Health Symposium: People, plants and animals (September 15, 2010; ISU, Ames, IA)

2010: Organizing committee member and session moderator: RNA in Motion Symposium (September 9-12, 2010; Ames, IA)

Editorial board 

  1. Frontiers in Cellular Neuroscience, Guest Editor (2025-2026)
  2. Gene Therapy, Editorial Board Member (Since 2020)
  3. Biochimica et Biophysica Acta-Gene Regulatory Mechanisms, Guest Editor, Special issue “Role of RNA Structure in Splicing” (Published in 2019) 
  4. Scientific Reports (Nature), Editorial Board Member (Since 2016)
  5. Biochimica et Biophysica Acta-Gene Regulatory Mechanisms, Editorial Board Member (Since 2016)
  6. PLoS One, Academic Editor (Since 2015)
  7. Frontiers of Biosciences, Managing Editor (Since 2007)

Memberships

Professional memberships 

2017-           : The RNA Society of Gene & Cell Therapy

2012-           : Oligonucleotide Therapeutic Society (OTS) 

2012-           : American Society for Cell Biology (ASCB)

2013-           : American Society for Human Genetics (ASHG)

2010-           : Society for Neuroscience (SfN)

2010-           : American Association for Advancement of Science (AAAS)

2009-           : Osborne Club, Iowa State University

2009-           : The Genetics Society of America (GSA)

2005-           : American Society for Microbiology (ASM)

2003-           : The RNA Society

Selected Publications

Scholarly and professional links: 

Google Scholar

MyNCBI

ORCiD 

https://en.wikipedia.org/wiki/Ravindra_N._Singh

Publications

  1. Ottesen EW, Murzyn WA, Kaas RL, Bertrand KJ, Payne JL, Singh RN (2026). A therapeutic antisense oligonucleotide encompassing 2′-O-methoxyethyl modification triggers unique perturbation of the transcriptome. NAR Mol Med. 3(1):ugag002
  2. Singh NN, Luo D, Singh RN (2025) Pre-mRNA splicing modulation by antisense oligonucleotides. Methods Mol Biol. 2964, 381-404. 
  3. Ottesen EW, Singh RN (2025). Different factors underlie mild and severe forms of spinal muscular atrophy. Brain 148, 360-362. 
  4. Ottesen EW, Singh NN, Seo J, Singh RN (2024). U1 snRNA interactions with deep intronic sequences regulate splicing of multiple exons of spinal muscular atrophy genes. Front. Neurosci. 18:1412893. 
  5. Luo D, Ottesen EW, Lee JH, Singh RN (2024). Transcriptome- and proteome-wide effects of a circular RNA encompassing four early exons of the spinal muscular atrophy genes. Sci Rep. 14(1):10442. 
  6. Ottesen EW, Seo J, Luo D, Singh NN, Singh RN (2024). A super minigene with a short promoter and truncated introns recapitulates essential features of transcription and splicing regulation of the SMN1 and SMN2 genes. Nucleic Acids Research 52(7):3547-3571.
  7. Ottesen EW, Singh RN (2024)Synergistic Effect of an Antisense Oligonucleotide and Small Molecule on Splicing Correction of the Spinal Muscular Atrophy Gene. Neuroscience Insights. 19:26331055241233596. 
  8. Ottesen EW, Singh NN, Luo D, Kaas B, Gillette BJ, Seo J, Jorgensen HJ, Singh RN (2023). Diverse targets of SMN2-directed splicing-modulating small molecule therapeutics for spinal muscular atrophy. Nucleic Acids Research 51(12):5948-5980
  9. Singh NN, O'Leary CA, Eich T, Moss WN, Singh RN (2022). Structural Context of a Critical Exon of Spinal Muscular Atrophy Gene. Front Mol Biosci. 9:928581.
  10. Rossoll W, Singh RN (2022). Current status of gene therapy for spinal muscular atrophy. Front. Cell. Neurosci. 16:916065. doi: 10.3389/fncel.2022.916065
  11. Luo D, Singh NN, Singh RN (2022). Internal Introns Promote Backsplicing to Generate Circular RNAs from Spinal Muscular Atrophy Gene. Genes (Basel) 13(7):1145. doi: 10.3390/genes13071145.
  12. Ottesen EW, Luo D, Singh NN, Singh RN (2021).  High Concentration of an ISS-N1-Targeting Antisense Oligonucleotide Causes Massive Perturbation of the Transcriptome. Int J Mol Sci. 22(16):8378. doi: 10.3390/ijms22168378. 
  13. Singh NN, Hoffman S, Reddi PP, Singh RN (2021). Spinal muscular atrophy: Broad disease spectrum and sex-specific phenotypes. Biochim Biophys Acta Mol Basis Dis. 1867(4):166063. doi: 10.1016/j.bbadis.2020.166063.
  14. Singh RN, Ottesen EW, Singh NN (2020). The First Orally Deliverable Small Molecule for the Treatment of Spinal Muscular Atrophy. Neurosci Insights. 15:2633105520973985. doi: 10.1177/2633105520973985.
  15. Singh RN, Seo J, Singh NN (2020). RNA in spinal muscular atrophy: Therapeutic implications of targeting. Expert Opin Ther Targets. 1-13. doi:10.1080/14728222.2020.1783241.
  16. Ottesen EW, Singh RN (2020) Characteristics of circular RNAs generated by human Survival Motor Neuron genes. Cell Signal 73: 109696. 
  17. Singh NN, Ottesen EW, Singh RN (2020) A survey of transcripts generated by spinal muscular atrophy genes. Biochim Biophys Acta-Gene Regulatory Mechanisms 1863: 12. 
  18. Singh NN, Singh RN (2019) How RNA structure dictates the usage of a critical exon of spinal muscular atrophy gene. Biochim Biophys Acta-Gene regulatory mechanisms. 1862(11-12). pii: S1874-9399(18)30510-8.
  19. Singh RN, Singh NN (2019). A novel role of U1 snRNP: Splice site selection from a distance. Biochim Biophys Acta-Gene regulatory mechanisms. 1862(6):634-64
  20. Ottesen EW, Luo D, Seo J, Singh NN, Singh RN (2019). Human Survival Motor Neuron genes generate a vast repertoire of circular RNAs.  Nucleic Acids Research. 47(6):2884-2905. 
  21. Singh RN (2019) More is needed to complement the available therapies of spinal muscular atrophy gene. Future Med Chem. 11(22):2873-2876. 
  22. Baralle FE, Singh RN, Stamm S (2019). RNA structure and splicing regulation. Biochim Biophys Acta-Gene regulatory mechanisms. 1862(11-12):194448.
  23. Ottesen EW, Singh NN, Luo D, Singh RN (2018). High-affinity RNA targets of Survival Motor Neuron Protein reveals diverse preferences for sequence and structural motifs.  Nucleic Acids Research 46 (20), 10983-11001.
  24. Singh RN, Singh NN (2018) Mechanism of splicing regulation of spinal muscular atrophy genes. Advances in Neurobiology 20, 31-61.
  25. Singh NN, Luo D, Singh RN (2018) Splicing modulation by antisense oligonucleotides. Methods in Molecular Biology 1828, 415-437. 
  26. Ottesen EW, Seo J, Singh NN, Singh RN (2017). A multilayered control of the human Survival Motor Neuron gene expression by Alu elements. Frontiers in Microbiology 8, 2252.
  27. Singh NN, Del Rio-Malewski JB, Luo D, Ottesen EW, Howell MD, Singh RN (2017). Activation of a cryptic 5¢ splice site reverses the impact of pathogenic splice site mutations in the spinal muscular atrophy gene. Nucleic Acids Research 45(21), 12214-12240.
  28. Howell MD, Ottesen EW, Singh NN, Anderson RL, Seo J, Sivanesan S, Whitley EM, Singh RN (2017). TIA1 is a gender-specific disease modifier of a mild mouse model of spinal muscular atrophy. Scientific Reports 7, 7183.
  29. Singh NN, Howell MD, Androphy EJ, Singh RN (2017). How the discovery of ISS-N1 led to the first medical therapy for spinal muscular atrophy. Gene Therapy 24, 520-526.
  30. Howell MD, Ottesen EW, Singh NN, Anderson RL, Singh RN (2017). Gender-Specific Amelioration of SMA Phenotype upon Disruption of a Deep Intronic Structure by an Oligonucleotide. Molecular Therapy 5, 1328-1341. 
  31. Singh NN, Howell MD, Ottesen EW, Singh RN (2017) Diverse role of survival motor neuron protein. Biochim Biophys Acta 1860(3):299-315
  32. Singh NN, Howell MD, Singh RN (2016) Transcription and splicing regulation of spinal muscular atrophy genes. In: Sumner CJ, Paushkin S, Ko C-P (eds). Spinal Muscular Atrophy: Disease Mechanisms and Therapy. Academic Press, 2017, pp 75–97.
  33. Seo J, Singh NN, Ottesen EW, Lee BM, Singh RN (2016). A novel human-specific splice isoform alters the critical C-terminus of Survival Motor Neuron protein. Scientific Reports 6, 30778.
  34. Seo J, Singh NN, Ottesen EW, Sivanesan S, Shishimorova M, Singh RN (2016). Oxidative stress triggers body-wide skipping of multiple exons of spinal muscular atrophy gene. PLoS One 11, e0154390.
  35. Ottesen EW, Howell MD, Singh, NN, Seo J, Whitley EM, Singh RN (2016). Severe impairment of male reproductive organ development in a low SMN expressing mouse model of spinal muscular atrophy. Scientific Reports 6, 20193.
  36. Singh NN, Lee BM, DiDonato CJ, Singh RN (2015). Mechanistic principles of antisense targets for the treatment of spinal muscular atrophy. Future Medicinal Chemistry 7, 1793-808
  37. Singh NN, Lee BM, Singh RN (2015). Splicing regulation in spinal muscular atrophy by a RNA structure formed by long distance interactions. Annals of NY Academy of Sciences 1341, 176-87.
  38. Kiel JM, Seo J, Howell MD, Hsu WH, Singh RN* and DiDonato CJ* (2014). A short antisense oligonucleotide ameliorates symptoms of severe mouse models of spinal muscular atrophy. Molecular Therapy-Nucleic Acids 3, e174.*Co-corresponding authors
  39. Howell MD, Singh NN, Singh RN (2014). Advances in therapeutic development for spinal muscular atrophy. Future Medicinal Chemistry 9, 1081-1099. 
  40. Seo J, Ottesen EW, Singh RN (2014) Antisense methods to modulate pre-mRNA splicing. Methods in Molecular Biology 1126, 271-283.
  41. Seo J, Howell MD, Singh NN, Singh RN (2013). Spinal muscular atrophy: An update on therapeutic progress. Biochim Biophys Acta 1832, 2180-2190. 
  42. Singh NN, Lawler MN, Ottesen EW, Upreti D, Kaczynski JR, Singh RN (2013). An intronic structure enabled by a long-distance interaction serves as a novel target for splicing correction in spinal muscular atrophy. Nucleic Acids Research 41, 8144-8165.
  43. Sivanesan S, Howell MD, DiDonato CJ, Singh RN (2013). Antisense oligonucleotide mediated therapy of spinal muscular atrophy. Translational Neuroscience 4, 1-7.
  44. Singh NN, Seo J, Rahn S, Singh RN (2012). A multi-exon-skipping detection assay reveals surprising diversity of splice isoforms of spinal muscular atrophy genes. PLoS One 7 (11):e49595.
  45. Singh RN, Singh NN (2012) Functional analysis of large exonic sequences through iterative in vivo selection. Book Chapter 18, pp 201-209, in “Methods in alternative splicing”. Publishers: Wiley-VCH Verlag GmBH &Co.
  46. Singh NN, Seo J, Singh RN (2012) Identification of splicing cis-elements through an ultra-refined antisense microwalk. Book Chapter 19, pp 211-217, in “Methods in alternative splicing”. Publishers: Wiley-VCH Verlag GmBH &Co.
  47. Singh NN, Singh RN (2011) Alternative splicing in spinal muscular atrophy underscores the role of an intron definition model. RNA Biology 8, 600-606.
  48. Singh NN, Seo J, Ottesen EW, Shishimorova M, Bhattacharya D, Singh RN (2011) TIA1 prevents skipping of a critical exon associated with spinal muscular atrophy.Molecular and Cellular Biology31, 935-954.
  49. Singh NN, Hollinger K, Bhattacharya D, Singh RN (2010) An antisense microwalk reveals critical role of an intronic position linked to a unique long-distance interaction in pre-mRNA splicing. RNA 16, 1167-1181.
  50. Papp LV, Lu J, Bolderson E, Boucher D, Singh R, Holmgren A, Khanna KK (2010) SECIS binding protein 2 promotes cell survival by protecting against oxidative stress. Antioxidants and Redox Signaling 12, 797-808.
  51. Singh NN, Shishimorova M, Cao LC, Gangwani L, Singh RN (2009) A short antisense oligonucleotide masking a unique intronic motif prevents skipping of a critical exon in spinal muscular atrophy. RNA Biology 6, 341-350.
  52. Papp LV, Wang J, Kennedy D, Boucher D, Zhang Y, Gladyshev VN, Singh RN, Khanna KK (2008) Functional characterization of alternatively spliced human SECISBP2 transcript variants. Nucleic Acids Research 36, 7192-206.
  53. Singh NN, Singh RN, Androphy EJ (2007) Modulating role of a RNA structure in skipping of a critical
exon in the spinal muscular atrophy genes. Nucleic Acids Research 35, 371-389.
  54. Singh RN (2007) Unfolding the mystery of alternative splicing through a unique method of in vivo selection. Frontiers in Bioscience 12, 3263-3272. 
  55. Singh RN (2007) Evolving concepts on human SMN pre-mRNA splicing. RNA Biology 4, 7-10. 
  56. Singh RN (2006) Association of severity of spinal muscular atrophy with the loss of NAIP gene. Neurology India 54, 246.
  57. Singh NK, Singh NN, Androphy EJ, Singh RN (2006) Splicing of a Critical Exon of Survival Motor Neuron genes is regulated by a human-specific silencer element located in the last intron. Molecular and Cellular Biology 26, 1333-1346.
  58. Singh NN, Androphy EJ, Singh RN (2004) Regulation and regulatory activities of alternative splicing of the SMN genes. Critical Reviews in Eukaryotic Gene Expression14, 271-285.
  59. Singh NN, Androphy EJ, Singh RN (2004) An extended inhibitory context causes skipping of exon 7 of SMN2 in spinal muscular atrophy. Biochemical and Biophysical Research Communications 315, 381-388.
  60. Singh NN, Androphy EJ, Singh RN (2004) In vivo selection reveals features of combinatorial control that defines a critical exon in the spinal muscular atrophy genes. RNA 10, 1291-1305.
  61. Singh RN, Saldanha R, D’Souza LM, Lambowitz AM (2002) Binding of a group II intron-encoded reverse transcriptase/maturase to its high affinity intron RNA binding site involves sequence-specific recognition and autoregulates translation. Journal of Molecular Biology 318, 287-303.
  62. Wank H, SanFilippo J, Singh RN, Matsuuara M, Lambowitz AM (1999) A reverse transcriptase/maturase promotes RNA splicing by binding at its own coding segment in a group II intron. Molecular Cell 4, 239-250.
  63. Rao UR, Chapman MR, Singh RN, Mehta K, Klei TR (1999) Transglutaminase activity in equine strongyles and its potential role in growth and development. Parasite 6, 131-139.
  64. Singh RN, Dreher TW (1998) Specific site selection in RNA resulting from a combination of nonspecific secondary structure and -CCR- boxes: initiation of minus strand synthesis by turnip yellow mosaic virus RNA-dependent RNA polymerase. RNA 4, 1083-1095.
  65. Singh RN, Dreher TW (1997) Turnip Yellow Mosaic Virus RNA-dependent RNA polymerase: Initiation of minus strand synthesis in vitro. Virology233, 430-439.
  66. Lustigman S, Brotman B, Huima T, Castelhano AL, Singh RN, Mehta K and Prince AM (1995) Transglutaminase catalyzed reaction is important for molting of Onchocerca volvulus third-stage larvae. Antimicrobial Agents and Chemo Therapy 39, 1913-1919.
  67. Singh RN, McQueen T, Mehta K (1995) Detection of amine acceptor protein substrates of transglutaminase using 5-(biotinamido) pentylamine. Analytical Biochemistry 231, 261-263.
  68. Singh RN, Chandrashekar R and Mehta K (1995) Purification and partial characterization of a transglutaminase from dog filarial parasite Dirofilaria immitis. International Journal of Biochemistry and Cell Biology 27, 1285-1291.
  69. Singh RN, Mehta K (1994) Purification and characterization of a novel transglutaminase from filarial nematode Brugia malayi. European Journal of Biochemistry 225, 625-634.
  70. Singh RN, Akimenko VK (1994) Synergism among three purified cellulolytic components of Clostridium thermocellum. FEMS Microbiology Letters 122, 257-262.
  71. Singh RN, Akimenko VK (1994) Isolation and characterization of a complex forming hydrophilic endoglucanase of Clostridium thermocellum. Biochemistry and Molecular Biology International 32, 409-417.
  72. Singh RN, Akimenko VK (1993) Isolation of a cellobiohydrolase of Clostridium thermocellum capable of degrading natural crystalline substrates. Biochemical and Biophysical Research Communications 192, 1123-1130.
  73. Golovchenko NP, Singh RN, Velikodvorskaya GA, Akimenko VK (1993) Isolation and characterization of a lichenan degrading hydrophobic endoglucanase from Clostridium thermocellum. Applied Microbiology and Biotechnology 39, 74-79.
  74. Aminov RI, Golovchenko NP, Singh RN, Akimenko VK (1993) Specific proteolysis of Clostridium thermocellum endoglucanase upon heterologous expression in Escherichia coli cells. Genetika (In Russian) 29, 217-224.
  75. Singh RN, Balakrishna K, Varma AK (1992) Refuge for Reuse. Science Reporter 29, 19-22.

Patents

  1. Singh RN and Singh NN (2013) A deep intronic target for splicing correction on spinal muscular atrophy gene. (World patent WO/2014/113540) (US patent 20150315582). 
  2. Singh RN and Singh NN (2011) Spinal Muscular Atrophy gene treatment via targeting SMN2 catalytic core. (US patent 20110269820).
  3. Singh RN, Singh NK, Singh NN and Androphy EJ (2007) Spinal Muscular Atrophy (SMA) treatment via targeting of SMN2 splice site inhibitory sequences. (US patent # 7,838,657). This antisense target currently licensed to IONIS Pharmaceuticals/Biogen has produced the first FDA-approved drug (SpinrazaTM/Nusinersen) for SMA.
  4. Singh RN, Singh NN and Androphy EJ (2004) Exon Analysis. World patent publication # WO/2004/113867.