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Chemistry

Faculty

Matthew D. Disney, Ph.D.

Professor
Department of Chemistry
Florida Campus
Laboratory Website
disney@scripps.edu
(561) 228-2203

Scripps Research Joint Appointments

Faculty, Graduate Program

Research Focus

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. 

Education

Ph.D., Biophysical Chemistry, University of Rochester, 2003
M.S., Chemistry, University of Rochester, 1999
B.S., Chemistry, University of Maryland, College Park, 1997

Awards & Professional Activities

1995 – 1997- Howard Hughes Medical Institute Undergraduate Research Fellow; University of Maryland, College Park.
1997- Eric A. Batista Award; University of Maryland, College Park. Award for most outstanding undergraduate research.
1997 – 1999 - Sherman-Clark Memorial Fellow; University of Rochester.
2000 – 2001 - Elon Huntington Hooker Memorial Fellow; University of Rochester.
2001 – 2002 - Arnold Weissberger Memorial Fellow; University of Rochester.
June 2003 – May 2004 - Roche Foundation Post doctoral Fellowship; Swiss Federal Institute of Technology (ETH, Zürich).
June 2004 – January 2005 - Second Year Roche Foundation Post doctoral Fellowship; Swiss Federal Institute of Technology (ETH, Zürich).
September 2005 – August 2010 - Camille and Henry Dreyfus New Faculty Award.
July 2007 – June 2009 - NYSTAR JD Watson Young Investigator Award.
July 2008 – June 2010 - Research Corporation Cottrell Scholar Award.
May 2010 – April 2015 - Dreyfus Teacher-Scholar Award.
May 2010 - University at Buffalo, Excellent Scholar, Young Investigator Award.
2012 - David Gin Award in Carbohydrate Chemistry from the American Chemical Society in recognition of excellence in carbohydrate chemistry from a new investigator.
2013 - Eli Lilly Award in Biological Chemistry from American Chemical Society in recognition of outstanding research in biological chemistry of unusual merit and independence of thought and originality.

Selected References

Structure and Dynamics of RNA Repeat Expansions That Cause Huntington's Disease and Myotonic Dystrophy Type 1. Chen JL, VanEtten DM, Fountain MA, Yildirim I, Disney MDBiochemistry. 2017 Jul 11;56(27):3463-3474.

Inhibiting Translation One Protein at a Time. Disney MDTrends Biochem Sci. 2017 Jun;42(6):412-413.

Defining RNA-Small Molecule Affinity Landscapes Enables Design of a Small Molecule Inhibitor of an Oncogenic Noncoding RNA. Velagapudi SP, Luo Y, Tran T, Haniff HS, Nakai Y, Fallahi M, Martinez GJ, Childs-Disney JL, Disney MDACS Cent Sci. 2017 Mar 22;3(3):205-216.

Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis. Gendron TF, Chew J, Stankowski JN, Hayes LR, Zhang YJ, Prudencio M, Carlomagno Y, Daughrity LM, Jansen-West K, Perkerson EA, O'Raw A, Cook C, Pregent L, Belzil V, van Blitterswijk M, Tabassian LJ, Lee CW, Yue M, Tong J, Song Y, Castanedes-Casey M, Rousseau L, Phillips V, Dickson DW, Rademakers R, Fryer JD, Rush BK, Pedraza O, Caputo AM, Desaro P, Palmucci C, Robertson A, Heckman MG, Diehl NN, Wiggs E, Tierney M, Braun L, Farren J, Lacomis D, Ladha S, Fournier CN, McCluskey LF, Elman LB, Toledo JB, McBride JD, Tiloca C, Morelli C, Poletti B, Solca F, Prelle A, Wuu J, Jockel-Balsarotti J, Rigo F, Ambrose C, Datta A, Yang W, Raitcheva D, Antognetti G, McCampbell A, Van Swieten JC, Miller BL, Boxer AL, Brown RH, Bowser R, Miller TM, Trojanowski JQ, Grossman M, Berry JD, Hu WT, Ratti A, Traynor BJ, Disney MD, Benatar M, Silani V, Glass JD, Floeter MK, Rothstein JD, Boylan KB, Petrucelli L. Sci Transl Med. 2017 Mar 29;9(383). pii: eaai7866.

Small Molecule Inhibition of microRNA-210 Reprograms an Oncogenic Hypoxic Circuit. Costales MG, Haga CL, Velagapudi SP, Childs-Disney JL, Phinney DG, Disney MDJ Am Chem Soc. 2017 Mar 8;139(9):3446-3455.

Rational Design of Small Molecules Targeting Oncogenic Noncoding RNAs from Sequence. Disney MD, Angelbello AJ. Acc Chem Res. 2016 Dec 20;49(12):2698-2704.

Precise small-molecule recognition of a toxic CUG RNA repeat expansion. Rzuczek SG, Colgan LA, Nakai Y, Cameron MD, Furling D, Yasuda R, Disney MDNat Chem Biol. 2017 Feb;13(2):188-193.

Rapid Generation of miRNA Inhibitor Leads by Bioinformatics and Efficient High-Throughput Screening Methods. Haga CL, Velagapudi SP, Childs-Disney JL, Strivelli J, Disney MD, Phinney DG. Methods Mol Biol. 2017;1517:179-198.

Development of pharmacophore models for small molecules targeting RNA: Application to the RNA repeat expansion in myotonic dystrophy type 1. Angelbello AJ, González ÀL, Rzuczek SG, Disney MDBioorg Med Chem Lett. 2016 Dec 1;26(23):5792-5796.

Controlled dehydration improves the diffraction quality of two RNA crystals. Park H, Tran T, Lee JH, Park H, Disney MDBMC Struct Biol. 2016 Nov 3;16(1):19.

Corrigendum: A Toxic RNA Catalyzes the In Cellulo Synthesis of Its Own Inhibitor. Rzuczek SG, Park H, Disney MDAngew Chem Int Ed Engl. 2016 Aug 16;55(34):9817. 

Chemistry and Chemical Biology of Therapeutically Important Compounds. Disney MDBioorg Med Chem. 2016 Sep 1;24(17):3875. 

Small Molecule Recognition and Tools to Study Modulation of r(CGG)(exp) in Fragile X-Associated Tremor Ataxia Syndrome. Yang WY, He F, Strack RL, Oh SY, Frazer M, Jaffrey SR, Todd PK, Disney MDACS Chem Biol. 2016 Sep 16;11(9):2456-65. 

Design of a bioactive small molecule that targets r(AUUCU) repeats in spinocerebellar ataxia 10. Yang WY, Gao R, Southern M, Sarkar PS, Disney MDNat Commun. 2016 Jun 1;7:11647.

Design of a small molecule against an oncogenic noncoding RNA. Velagapudi SP, Cameron MD, Haga CL, Rosenberg LH, Lafitte M, Duckett DR, Phinney DG, Disney MDProc Natl Acad Sci U S A. 2016 May 24;113(21):5898-903. 

Comparison of small molecules and oligonucleotides that target a toxic, non-coding RNA. Costales MG, Rzuczek SG, Disney MDBioorg Med Chem Lett. 2016 Jun 1;26(11):2605-9. 

Inforna 2.0: A Platform for the Sequence-Based Design of Small Molecules Targeting Structured RNAs. Disney MD, Winkelsas AM, Velagapudi SP, Southern M, Fallahi M, Childs-Disney JL. ACS Chem Biol. 2016 Jun 17;11(6):1720-8. 

Analysis of secondary structural elements in human microRNA hairpin precursors. Liu B, Childs-Disney JL, Znosko BM, Wang D, Fallahi M, Gallo SM, Disney MDBMC Bioinformatics. 2016 Mar 1;17:112.

Small Molecule Targeting of a MicroRNA Associated with Hepatocellular Carcinoma. Childs-Disney JL, Disney MDACS Chem Biol. 2016 Feb 19;11(2):375-80.

Approaches to Validate and Manipulate RNA Targets with Small Molecules in Cells. Childs-Disney JL, Disney MDAnnu Rev Pharmacol Toxicol. 2016;56:123-40. 

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.

Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in Fragile X syndrome. Colak D, Zaninovic N, Cohen MS, Rosenwaks Z, Yang W-Y, Gerhardt J, Disney MD, Jaffrey SR. Science, 2014, 343:1002-1005. PMID: 24578575.

Targeting the r(CGG) repeats that cause FXTAS with modularly assembled small molecules and oligonucleotides. Tran T, Childs-Disney JL, Liu B, Guan L, Rzuczek S, Disney MDACS Chemical Biology, 2014, 9:904-912. PMID: 24506227.

Two-dimensional combinatorial screening enables the bottom-up design of a microRNA-10b inhibitor. Velagapudi SP, Disney MDChemical Communications, 2014, 50:3027-3029. 

PMCID: PMC4040211.

Sequence-based design of bioactive small molecules that target precursor microRNAs. Velagapudi SP, Gallo SM, Disney MDNature Chemical Biology, 2014, 10:291-297. PMCID: PMC3962094.

Myotonic Dystrophy Type 2 RNA: Structural Studies and Designed Small Molecules that Modulate RNA Function. Childs-Disney JL, Yildirim I, Park H, Lohman JR, Guan L, Tran T, Sarkar P, Schatz GC, Disney MDACS-Chemical Biology2014, 9:538-550. PMCID: PMC3944380.

Methods to enable the design of bioactive small molecules targeting RNA. Disney MD, Yildirim I, and Childs-Disney JL. Organic and Biomolecular Chemistry, 2014, 12:1029-1039. 

A chemoenzymatic route to diversify aminoglycosides enables a microarray-based method to probe acetyltransferase activity (Cover article). Tsitovich PB, Pushechnikov A, French JM, Disney MD. Chembiochem 2010, 11:1656-1660.

Structure-activity relationships through sequencing (StARTS) defines optimal and suboptimal RNA motif targets for small molecules. Velagapudi SP, Seedhouse SJ, Disney MD. Angew Chem Int Ed Engl. , 2010, 49:3816-3818.

Controlling the specificity of modularly assembled small molecules for RNA via ligand module spacing: targeting the RNAs that cause myotonic muscular dystrophy. Lee MM, Childs-Disney JL, Pushechnikov A, French JM, Sobczak K, Thornton CA, Disney MD. J Am Chem Soc., 2009, 131: 17464-17472.

Rational design of ligands targeting triplet repeating transcripts that cause RNA dominant disease: application to myotonic muscular dystrophy type 1 and spinocerebellar ataxia type 3. Pushechnikov A, Lee MM, Childs-Disney JL, Sobczak K, French JM, Thornton CA, Disney MD. J Am Chem Soc. 2009 Jul 22:131(28):9767-79.

Links

Targeting RNA

Podcast on rational design of small molecules targeting RNAs that cause incurable disease

Rational design of small molecules targeting incruable disease II

Rational design of small molecules targeting incruable disease

Highlight of our work on targeting toxic RNAs III

Highlight of our work on targeting toxic RNAs II

Highlight of our work on targeting toxic RNAs

Highlight on our work to target RNA Defects in Huntington's and other diseases

Podcast on our work on developing drugs for Myotonic Muscular Dystrophy

Letting the Drugs Have Their Say

MMD Research: Blocking Harmful Interactions