Faculty, Graduate Program
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.
Ph.D., Biophysical Chemistry, University of Rochester, 2003
B.S., Chemistry, University of Maryland, College Park, 1997
M.S., Chemistry, University of Rochester, 1999
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.
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 MD. ACS 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 MD. Chemical Communications, 2014, 50:3027-3029. PMCID: PMC4040211.
Sequence-based design of bioactive small molecules that target precursor microRNAs. Velagapudi SP, Gallo SM, Disney MD. Nature 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 MD. ACS-Chemical Biology, 2014, 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.