Disney, Matthew D. - The Scripps Research Institute

研究领域

The Disney group is focused on developing rational and predictable approaches to design highly selective therapeutics from only genome sequence. One of the major articulations of the utility of genome sequencing efforts has been in advancing patient-specific therapies, yet such developments have been only sparsely reported. We accomplish this lofty goal by using advancements in annotating RNA structure from sequence and several novel technologies that we have recently developed in our laboratory. Our current focus is on leveraging these technological advances to identify patient-specific therapies targeting orphan diseases that have no known cure or more common disorders to which there is a poor prognosis, such as drug resistant cancers. Key advances that we have recently reported include: (i) Developing lead therapeutics that improve defects associated with the most common adult-onset forms of muscular dystrophy (Myotonic Dystrophy Types 1 and 2) in both animal and cellular models of disease. (ii) Designing compounds that target the most common single gene cause of Autism (Fragile X Syndrome) and an adult-onset disease called Fragile X-Associated Tremor Ataxia Syndrome that occurs in older individuals that carry a shortened version of the Fragile X Syndrome genetic defect. These studies have advanced our understanding of novel roles of RNA-mediated gene silencing and in identifying and exploiting novel drug targets. (iii) Targeting the genetic defect that causes Huntington’s disease, which is an incurable disorder that causes muscle decline and cognitive issues. (iv) Correcting RNA processing defects that are caused by RNA mutations in Parkinsonism and Frontotemporal Dementia (FTDP-17). (v) Developing specific lead therapeutics that reduce the production of toxic proteins that are known to cause the majority of cases of Amyotrophic Lateral Sclerosis (ALS, Lou Gehrig’s disease) and Frontotemporal Dementia (vi) Designing precise therapeutics that specifically kill a variety of Cancers that have a poor prognosis with current chemotherapeutics (vii) Exploiting important classes of drug targets in multiple disorders that are viewed as being impossible to “drug” (viii) Developing and implementing novel technologies that allow for the precise reaction and cleavage of RNA targets by using small molecules to both identify and further manipulate therapeutically relevant RNAs by small molecules.

近期论文

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Su Z, Zhang Y, Gendron TF, Bauer PO, Chew J, Yang W-Y, Fostvedt E, Jansen-West K, Belzil VV, Desaro P, Johnston A, Overstreet K, Boeve BF, Dickson D, Floeter MK, Traynor BJ, Morelli C, Ratti A, Silani V, Rademakers R, Brown RH, Rothstein JD, Boylan KB, Petrucelli L*, Disney MD*. Biomarker and lead small molecule discovery to target r(GGGGCC)-associated defects in c9FTD/ALS. Neuron, in process. Rzuczek SG, Park H, Disney MD. A toxic RNA catalyzes the in cellulo synthesis of its own inhibitor. Angewandte Chemie, in press. Luo Y, Disney MD. Bottom-up design of small molecules that stimulate exon 10 skipping in mutant MAPT pre-mRNA. ChemBioChem, in press. Hoskins JW, Ofori LO, Chen CZ, Kumar A, Sobczak K, Nakamori M, Southall N, Patnaik S, Marugan JJ, Zheng W, Austin CP, Disney MD, Miller BL, Thornton CA. Lomofungin and dilomofungin: inhibitors of MBNL1-CUG RNA binding with distinct cellular effects. Nucleic Acids Research (2014), 42, 6591-602. doi: 10.1093/nar/gku275. PMCID: PMC4041448. Colak D, Zaninovic N, Cohen MS, Rosenwaks Z, Yang WY, Gerhardt J, Disney MD, Jaffrey SR. Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome. Science (2014), 343, 1002-5. doi: 10.1126/science.1245831. PMID: 24578575. Tran T, Childs-Disney JL, Liu B, Guan L, Rzuczek S, Disney MD. Targeting the r(CGG) Repeats That Cause FXTAS with Modularly Assembled Small Molecules and Oligonucleotides. ACS Chemical Biology (2014), 9, 904-12. doi: 10.1021/cb400875u. PMID: 24506227. Velagapudi SP, Disney MD. Two-dimensional combinatorial screening enables the bottom-up design of a microRNA-10b inhibitor. Chemical Communications (2014), 50, 3027-9. doi: 10.1039/c3cc00173c. ??PMCID: PMC4040211. Velagapudi SP, Gallo SM, Disney MD. Sequence-based design of bioactive small molecules that target precursor microRNAs. Nature Chemical Biology (2014), 10, 291-7. doi: 10.1038/nchembio.1452.?? PMCID: PMC3962094. Childs-Disney JL, Yildirim I, Park H, Lohman JR, Guan L, Tran T, Sarkar P, Schatz GC, Disney MD. Structure of the myotonic dystrophy type 2 RNA and designed small molecules that reduce toxicity. ACS Chemical Biology (2014), 9, 538-50. doi: 10.1021/cb4007387. PMCID: PMC3944380. Disney MD, Yildirim I, and Childs-Disney JL. Methods to enable the design of bioactive small molecules targeting RNA. Organic and Biomolecular Chemistry (2014), 12, 1029-39. doi: 10.1039/c3ob42023j.?? Disney MD. Rational design of chemical genetic probes of RNA function and lead therapeutics targeting repeating transcripts. Drug Discovery Today (2013), 18, 1228-36. doi: 10.1016/j.drudis.2013.07.024. PMCID: PMC3849211. Guan L, Disney MD. Covalent small molecule-RNA complex formation enables cellular profiling of small molecule-RNA interactions. Angewandte Chemie International Edition, English (2013), 52, 10010-3. doi: 10.1002/anie.201301639. PMCID: PMC3876275. Velagapudi SP, Disney MD. Defining RNA Motif-Aminoglycoside Interactions via Two-Dimensional Combinatorial Screening (2DCS) and Structure-Activity Relationships through Sequencing. Bioorganic and Medicinal Chemistry (2013), 21, 6132-8. doi: 10.1016/j.bmc.2013.04.072. PMCID: PMC3789863.?? Special issue on Nucleic Acids. Strack RL, Disney MD, Jaffrey SR. A superfolding Spinach2 reveals the dynamic nature of trinucleotide repeat-containing RNA. Nature Methods (2013), 10, 1219-24. doi: 10.1038/nmeth.2701. PMCID: PMC3852148. Rzuczek SG, Gao Y, Tang ZZ, Thornton CA, Kodadek T, Disney MD. Features of modularly assembled compounds that impart bioactivity against an RNA target. ACS Chemical Biology (2013), 8, 2312-21. doi: 10.1021/cb400265y. PMCID: PMC3876286. Velagapudi SP, Disney MD. Identifying And Characterizing RNA-Ligand Interactions Using 2-Dimensional Combinatorial Screening and Structure-Activity Relationships Through Sequencing. In Methods for Studying Nucleic Acid/drug Interactions, (2012), CRC Press; Taylor & Francis Group, Boca Raton, FL, ISBN-10: 1439839735, ISBN-13: 978-1439839737.?? Childs-Disney JL, Stepniak-Konieczna E, Tran T, Yildirim I, Park H, Chen CZ, Hoskins J, Southall N, Marugan JJ, Patnaik S, Zheng W, Austin CP, Schatz GC, Sobczak K, Thornton CA, Disney MD. Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules. Nature Communications (2013), 4, 2044. doi: 10.1038/ncomms3044. PMCID: PMC3710115.?? Sellier C, Freyermuth F, Tabet R, Tran T, He F, Ruffenach F, Alunni V, Moine H, Thibault C, Page A, Tassone F, Willemsen R, Disney MD, Hagerman PJ, Todd PK, Charlet-Berguerand N. Sequestration of DROSHA and DGCR8 by expanded CGG-repeats RNA alters microRNA processing in Fragile X-Associated Tremor/Ataxia Syndrome. Cell Reports (2013), 3, 869-80. PMCID: PMC3639429?? Yildirim I, Park H, Disney MD, Schatz GC. A Dynamic Structural Model of Expanded RNA CAG Repeats: A Refined X-ray Structure and Computational Investigations Using Molecular Dynamics and Umbrella Sampling Simulations. Journal of the American Chemical Society (2013), 135, 3528-38. PMCID: PMC3625063 Childs-Disney JL, Parkesh R, Nakamori M, Thornton CA, Disney MD. Rational Design of Bioactive, Modularly Assembled Aminoglycosides Targeting the RNA that Causes Myotonic Dystrophy Type 1. ACS Chemical Biology (2012), 7, 1984-93. PMCID: PMC3528830??