Matthew D. Disney, PhD

Professor
Department of Chemistry
Florida Campus


 Email

Scripps Research Joint Appointments

Faculty, Graduate Program

Research Focus

Research Focus

The Disney group develops rational approaches to design selective therapeutics from only genome sequence. One of the major advantages that genome sequencing efforts potentially provides is advancing patient-specific therapies, yet such developments have been only sparsely reported. We have developed general approach to provide lead Targeted Therapeutics and Precise Medicines that target RNAs that cause disease broadly and include rare neuromuscular (muscular dystrophy), neurodegenerative (Alzheimer’s, ALS), infectious diseases as well as difficult-to-treat cancers (breast, pancreatic, prostate, and others), and infectious diseases that can emerge through seasonal exposures.  Designed compounds have demonstrated activity in human derived cellular disease models as well as pre-clinical animal models of disease.  We train the next-generation of scientists to ensure our work has an exponential impact in studying disease biology and leveraging it into making Precision Medicines.

To achieve these goals, we developed a proprietary platform dubbed Inforna over the past 13 years.  It merges chemoinformatics and RNA structure to identify lead compounds that target an RNA of interest; that is, Inforna houses a database of RNA three dimensional motifs that bind small molecule medicines, identified via an experimental library-versus-library screen. The bioinformatics pipeline rapidly and accurately identifies disease-associated RNA sequences that adopt targetable three-dimensional folds by comparison to the database.  This pipeline has been validated in various peer-review publications that demonstrated that the platform can be used to target RNAs that cause neuromuscular, neurodegenerative, and infectious diseases as well as difficult-to-treat cancers in pre-clinical animal models.  Additionally, lead small molecule medicines can also be rapidly developed into compounds that recruit cellular nucleases to selectively destroy the RNAs that cause these diseases in a catalytic and substoichiometric manner (e.g. one molecule of the small molecule cleaves more than one molecule of the RNA target) coined RIBOTACs.  Two of the major perceived concerns in the area of RNA-targeted small molecules are selectivity and potency.  We have broadly demonstrated that these issues can be rapidly overcome via rational design and fragment assembly.  

Key recent advances include:

(i) Sequence-based drug design across the human transcriptome to provide precision lead medicines 

(ii) Small molecule cleavage of RNAs (RIBOTACS) in a catalytic and sub-stoichiometric manner via recruitment of cellular nucleases

(iii) Tools and technologies to study ligand binding capacity of RNAs across the transcriptome (Chem-CLIP and Ribo-SNAP)

(iv) Showing broad classes of known drugs target RNA and that their activity may be traced to targeting non-coding RNA

(v) Chemical biology approaches to understand RNA biology.  We uncovered the mechanistic cause of Fragule X-Syndrome and Autism and also can define precisely the effect that non-coding RNAs have on the proteome.

(vi) Study druggability broadly. We have the ability to answer fundamental questions about how druggable the genome really is.  Thus, we have launched the Druggable Transcriptome Project.


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

Professional Experience

2005-2010 Assistant Professor, University at Buffalo, The State University of New York
2002-2005 Postdoctoral Fellow, Swiss Federal Institute of Technology Zurich (ETH)

2005-2010 Assistant Professor, University at Buffalo, The State University of New York
2002-2005 Postdoctoral Fellow, Swiss Federal Institute of Technology Zurich (ETH)

Awards & Professional Activities

2018 - BioFlorida Entrepreneur of the Year.

2018 - Barry Cohen Prize. Awarded by the Medicinal Chemistry Section of the Israel Chemical Society and Teva Pharmaceutical Industries. 

2017 - Scripps Florida Outstanding Mentor Award. 

2016 - Tetrahedron Young Investigator Award in Bioorganic and Medicinal Chemistry.

2015 - NIH Director’s Pioneer Award.

2015, 2016, 2017 - Blavatnik Young Scientists Award Finalist.

2014 - David W. Robertson Award in Medicinal Chemistry. Awarded by the American  Chemical Society’s Division of Medicinal Chemistry for having a primary role in the discovery of a novel therapeutic agents, targets, theoretical concepts in medicinal chemistry or drug discovery, and making a significant scientific discovery that enhances the field of medicinal chemistry.

2013 - Excellence Award in the field of Research in Science and Technology. India-US Chamber of Commerce, Inc., South Florida.  

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.

2012 - David Gin Award in Carbohydrate Chemistry from the American Chemical Society in recognition of excellence in carbohydrate chemistry from a new investigator.

May 2010 - University at Buffalo, Excellent Scholar, Young Investigator Award.

May 2010 – April 2015 - Dreyfus Teacher-Scholar Award.

July 2008 – June 2010 - Research Corporation Cottrell Scholar Award.

July 2007 – June 2009 - NYSTAR JD Watson Young Investigator Award.

September 2005 – August 2010 - Camille and Henry Dreyfus New Faculty Award.

June 2004 – January 2005 - Second Year Roche Foundation Post doctoral Fellowship; Swiss Federal Institute of Technology (ETH, Zürich).

June 2003 – May 2004 - Roche Foundation Post doctoral Fellowship; Swiss Federal Institute of Technology (ETH, Zürich).

2001 – 2002 - Arnold Weissberger Memorial Fellow; University of Rochester.

2000 – 2001 - Elon Huntington Hooker Memorial Fellow; University of Rochester.

1997 – 1999 - Sherman-Clark Memorial Fellow; University of Rochester.

1997- Eric A. Batista Award; University of Maryland, College Park. Award for most outstanding undergraduate research.

1995 – 1997- Howard Hughes Medical Institute Undergraduate Research Fellow; University of Maryland, College Park.

Selected References

All Publications

Small Molecule Targeted Recruitment of a Nuclease to RNA. Costales MG, Matsumoto Y, Velagapudi SP, Disney MDJ Am Chem Soc. 2018 May 24. doi: 10.1021/jacs.8b01233. [Epub ahead of print]. PMID: 29792692.

Using Genome Sequence to Enable the Design of Medicines and Chemical Probes. Angelbello AJ, Chen JL, Childs-Disney JL, Zhang P, Wang ZF, Disney MDChem Rev. 2018 Feb 28;118(4):1599-1663. doi: 10.1021/acs.chemrev.7b00504. Epub 2018 Jan 11. PMID: 29322778.

Bleomycin Can Cleave an Oncogenic Noncoding RNA. Angelbello AJ, Disney MD. Chembiochem. 2017 Oct 30. doi: 10.1002/cbic.201700581. [Epub ahead of print] PubMed PMID: 29084369.

Small molecule alteration of RNA sequence in cells and animals. Guan L, Luo Y, Ja WW, Disney MD. Bioorg Med Chem Lett. 2017 Oct 18. pii: S0960-894X(17)31018-1. doi: 10.1016/j.bmcl.2017.10.034. [Epub ahead of print] PubMed PMID: 29079470.

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. 


Links

1. BioFlorida, 2018: Jupiter Chemist Matthew Disney Named BioFlorida's Entrepreneur of the Year

2. AAAS's EurekAlert!, 2018: Some Existing Anti-Cancer Drugs May Act in Part by Targeting RNA, Study Shows

3. AAAS's EurekAlert!, 2018: Novel RNA-Modifying Tool Corrects Genetic Diseases

4. C&EN, 2018: Expansion Therapeutics Launches to Target RNA with $55 Million: Start-Up will Develop Small Molecules Targeting RNA in the Muscle-Wasting Disease Myotonic Dystrophy

5. C&EN, 2017: The RNA Drug Hunters: Academics, Biotech Start-Ups, and Big Pharma Companies are Designing Small Molecules That Target RNA

6. The Myotonic Dystrophy Foundation, 2016: Rare Chemistry: Matt Disney Advances Development of Small Molecule Therapeutics for DM

7. The American Chemical Society's 2016 Drug Design and Delivery Symposium: Rational Design of Small Molecules Targeting RNA

8. NIH Director's Blog, 2016: Creative Minds - Can Diseased Cells Help to Make Their Own Drugs?

9. NewsHD.net, 2014: Scripps Florida Scientists Make Diseased Cells Synthesize Their Own Drug

10. ACS Chemical Biology Podcast, 2012: Dr. Matthew Disney on the Rational Design of Small Molecules Targeting RNAs that Cause Incurable Disease

11. ScienceDaily, 2012: Scientists Create Potent Molecules Aimed at Treating Muscular Dystrophy

12. C&EN, 2012: New Compound Corrects Badly Behaved RNA. (Targeting RNA: Small Molecule Binds to Trinucleotide Repeats Associated with Huntington’s Disease)

13. BioNews, 2012: Two RNA Studies Give Clues to Neurodegeneration

14. ScienceDaily, 2012: Scientists Create Novel RNA Repair Technology