Matthew D. Disney, Ph.D.
Faculty, Graduate Program
Ph.D., Biophysical Chemistry, University of Rochester, 2003
Department of Chemistry
Department of Neuroscience
Graduate Program Faculty Member, Kellogg School of Science and Engineering
The Scripps Research Institute
130 Scripps Way 2A2
Jupiter, Florida 33458
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, especially RNA-mediated neurological disorders, with 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:
- Developing approaches to chemically induce and reverse genetic diseases to precisely study their impact on cells (see: Nature Communications (2013), 4, 2044. doi: 10.1038/ncomms3044)
- 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. (see: Drug Discovery Today. (2013), 18, 1228-36. doi: 10.1016/j.drudis.2013.07.024)
- 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. (see: Science. (2014), 343, 1002-5. doi: 10.1126/science.1245831; ACS Chemical Biology. (2014), 9, 904-12. doi: 10.1021/cb400875u)
- Targeting the genetic defect that causes Huntington’s disease, which is an incurable disorder that causes muscle decline and cognitive issues. (see: ACS Chemical Biology. (2012), 7, 496-505. doi: 10.1021/cb200413a)
- Correcting RNA processing defects that are caused by RNA mutations that cause Parkinsonism and Frontotemporal Dementia (FTDP-17; see: ChemBioChem. (2014), in press. doi: 10.1002/cbic.201402069)
- 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 (see: Neuron. (2014), 83, 1043-50. doi: 10.1016/j.neuron.2014.07.041)
- Developed chemical approaches to allow for a diseased cell to synthesize its own drug, allowing new precision medicine strategies. (see: Angewandte Chemie International Edition English (2014), in press. doi: 10.1002/anie.201406465)
- Designing precise therapeutics that specifically kill a variety of Cancers that have a poor prognosis with current chemotherapeutics. (see: Nature Chemical Biology. (2014), 10, 291-7. doi: 10.1038/nchembio.1452)
- Exploiting important classes of drug targets in multiple disorders that are viewed as being impossible to “drug.”
- 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.
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 (2014), 83, 1043-1050. PMID: 25132468
Rzuczek SG, Park H, Disney MD. A toxic RNA catalyzes the in cellulo synthesis of its own inhibitor. Angew Chem Int Ed Engl (2014), doi: 10.1002/anie.201406465. PMID: 25164984
Luo Y, Disney MD. Bottom-up design of small molecules that stimulate exon 10 skipping in mutant MAPT pre-mRNA. ChemBioChem (2014), doi: 10.1002/cbic.201402069. PMID: 25115866
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 Res (2014), 42, 6591-602. 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. 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 Chem Biol (2014), 9, 904-12. PMID: 24506227.
Velagapudi SP, Disney MD. Two-dimensional combinatorial screening enables the bottom-up design of a microRNA-10b inhibitor. Chem Commun (Camb) (2014), 50, 3027-9. PMCID: PMC4040211.
Velagapudi SP, Gallo SM, Disney MD. Sequence-based design of bioactive small molecules that target precursor microRNAs. Nat Chem Biol (2014), 10, 291-7. 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 Chem Biol (2014), 9, 538-50. PMCID: PMC3944380.
Disney MD, Yildirim I, and Childs-Disney JL. Methods to enable the design of bioactive small molecules targeting RNA. Org Biomol Chem (2014), 12, 1029-39. PMCID: PMC4020623
Awards, Recognition, Appointments, and Honors
2016 Tetrahedron Young Investigator Award in Bioorganic and Medicinal Chemistry.
2015 National Institutes of Health Pioneer Award.
2015 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 Eli Lilly Award in Biological Chemistry. Awarded by the American Chemical Society’s Biological Chemistry Division for outstanding research in biological chemistry of unusual merit and independence of thought and originality.
2013 Excellence Award in the field of Research in Science and Technology. India-US Chamber of Commerce, Inc., South Florida.
2011 The American Chemical Society Division of Carbohydrate Chemistry David Y. Gin Award.
2011 University at Buffalo, Exceptional Scholar – Young Investigator Award.
2010 - 2015 Camille & Henry Dreyfus Teacher-Scholar Award.
2008 - 2011 Research Corporation Cottrell Scholar Award.
2007 - 2009 NYSTAR JD Watson Young Investigator Award
2005 - 2010 Camille & Henry Dreyfus New Faculty Award.
2004 - 2005 Second Year Roche Foundation Postdoctoral Fellowship; Swiss Federal Institute of Technology (ETH, Zürich).
2003 - 2004 Roche Foundation Postdoctoral 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.