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Molecular Medicine


Joel Gottesfeld, Ph.D.

Department of Molecular Medicine
California Campus
Laboratory Website
(858) 784-8913

Scripps Research Joint Appointments

Professor, Department of Chemistry
Faculty, Graduate Program

Research Focus

Chemical Regulation of Gene Expression

Research in our laboratory is concerned with development of therapeutics for the triplet-repeat neurodegenerative diseases Friedreich’s ataxia, myotonic dystrophy and Huntington’s disease. The location of these repeated sequences within their resident gene determines whether the disease will be due to epigenetic gene silencing (as in Friedreich's ataxia), RNA toxicity (as in myotonic dystrophy) or a toxic, gain-of-function protein (as in Huntington's disease).

Friedreich’s ataxia is caused by expansion of a GAA triplet repeat DNA sequence within an intron (a non-coding DNA sequence) of the gene for the essential mitochondrial protein frataxin (FXN). Frataxin is involved in energy production in cells, and loss of this protein leads to the disease. The repeats are known to silence the gene at the level of transcription into messenger RNA by formation of heterochromatin (epigenetic silencing). Since the repeats do not change the coding region of the gene, one therapeutic approach would be to find small molecules that would reactivate this silent gene. We identified a small molecule histone deacetylase inhibitor that is a potent inducer of FXN gene expression and frataxin protein in patient lymphoid cells. Importantly, these molecules up-regulate FXN expression in human neuronal cells derived from patient induced pluripotent stem cells and in two mouse models for the disease. Preclinical studies of safety and toxicity have been completed for one such compound and a phase I clinical trial in Friedreich’s ataxia patients has been performed, with no adverse side effects.  Importantly, the FXN gene was activated in lymphocytes taken from the patients, providing a first proof of concept. Further medicinal chemistry efforts have identified improved compounds with superior pharmacological properties for both Friedreich’s ataxia and Huntington’s disease.

With the advent of transcription factor reprogramming of human fibroblasts to induced pluripotent stem cells (iPSCs), we have taken advantage of this technology to derive cellular models for the triplet repeat diseases discussed above. Interestingly, the long repeats in Friedreich's ataxia and myotonic dystrophy iPSCs expand upon derivation and propagation of the iPSCs in culture. This finding has provided a cellular model for repeat instability, where we have implicated the mismatch repair pathway as a major component in repeat expansion. We are also studying the effects of small, DNA-binding pyrrole-imidazole polyamides as modulators of repeat expansion in both Friedreich's ataxia and myotonic dystrophy. Together, our studies point to new therapeutic opportunities for the triplet repeat diseases.


Ph.D., Biochemistry, California Institute of Technology, 1975

Professional Experience

Postdoc, 1978, Medical Research Council Laboratory of Molecular Biology, Cambridge, England

Awards & Professional Activities

Editorial Board: Associate Editor, Journal of Biological Chemistry

Selected References

For a complete list of publications:

Burnett, R., C. Melander, J.W. Puckett, L.S. Son, R.D. Wells, P.B. Dervan and J.M. Gottesfeld.  DNA sequence-specific polyamides alleviate transcription inhibition associated with long GAA-TTC repeats in Friedreich's ataxia.  Proc. Natl. Acad. Sci. USA, 103:11497-502, 2006; PMC1544198.

Herman, D., K. Jenssen, R. Burnett, E. Soragni, S. Perlman and J.M. Gottesfeld.  Histone deacetylase inhibitors reverse gene silencing in Friedreich's ataxia.  Nature Chem. Biol., 2: 551-558, 2006; PMID:16921367,

Rai, M. Soragni, E., K. Jenssen, R. Burnett, Herman, D., Coppola, G., Geschwind, D.H., Gottesfeld, J.M. and Pandolfo, M. HDAC inhibitors correct frataxin deficiency in a Friedreich ataxia mouse model.  PLoS ONE, Apr. 9:3(4):e1958, 2008. PMC1273517.

Thomas, E.A., Coppola, G., Desplats, P.A., Tang, B., Soragni, E., Burnett, R., Gao, F., Fitzgerald, K.M., Borok, J.F., Herman, D., Geschwind, D.H. and J.M. Gottesfeld. The HDAC inhibitor 4b ameliorates the  disease phenotype and transcriptional abnormalities in Huntington's disease transgenic mice.  Proc. Natl.  Acad. Sci. USA,105:15564-9, 2008; PMC2563081.

Ku, S., Soragni, E., Campau, E., Thomas, E.A., Altun, G., Laurent, L.C., Loring, J.F., Napierala, M. and J. Gottesfeld.  Friedreich's ataxia induced pluripotent stem cells model intergenerational GAATTC triplet repeat instability. Cell Stem Cell, 5:631-7, 2010; PMC2987635.

Du, J., Campau, E., Soragni, E., Ku, S., Puckett, J.W., Dervan, P.B. and J. M. Gottesfeld. Role of mismatch repair enzymes in GAA-TTC triplet-repeat expansion in Friedreich ataxia induced pluripotent stem cells. J. Biol. Chem., 287: 29861-29872, 2012; PMC3436184.

Molecular Medicine Seminar Series
Center for Physiological Proteomics
Department Contacts

CA Faculty

Asahara, Hiroshi
Balch, William E.
Boddy, Michael
Buxbaum, Joel
Catz, Sergio
Conti, Bruno
Cravatt, Benjamin
D'Lima, Darryl
DerMardirossian, Celine
Deryugina, Elena
Elias, Darlene
Encalada, Sandra
Felding, Brunhilde
Fowler, Velia
Friedlander, Martin
Gerace, Larry
Gottesfeld, Joel
Griffin, John
Hanneken, Anne
Heeb, Mary Jo
Henderson, Scott
Hoch, James
Johnson, Eric
Kanaji, Taisuke
Koziol, James
Lamia, Katja
Lipton, Stuart
Loring, Jeanne F.
Loskutoff, David
Lotz, Martin
Makarenkova, Helen P.
Mc Millan, Robert
Miles, Lindsey
Milner, Richard
Modena, Brian
Mosnier, Laurent
Nicholson, Laura
Paulson, James C.
Perego, Marta
Petrascheck, Michael
Pollard, Kenneth Michael
Quigley, James P.
Reed, Steven
Roberts, Edward
Rosen, Hugh
Ruggeri, Zaverio
Russell, Paul
Saez, Enrique
Smider, Vaughn
Srinivasan, Supriya
Steinhubl, Steven
Sutcliffe, J.
Tan, Eng
Topol, Eric
Vanderklish, Peter
Vogt, Peter K.
Wiseman, Luke
Wittenberg, Curt
Wolan, Dennis W.
Wu, Peng
Wu, Xiaohua
Yang, Xiang-Lei
Yates III, John

FL Faculty

Bannister, Thomas
Bohn, Laura M.
Cameron, Michael
Duckett, Derek
Gill, Matt
Griffin, Patrick
Hansen, Scott
Joazeiro, Claudio
Kamenecka, Theodore
Kissil, Joseph
Luo, Junli
McDonald, Patricia
Miller, Courtney
Niedernhofer, Laura
Phinney, Donald G.
Robbins, Paul
Scampavia, Louis
Schimmel, Paul
Smith, Roy
Spicer, Timothy

Affiliated Faculty

Cline, Hollis
Kojetin, Douglas
Lairson, Luke
Paegel, Brian
Rumbaugh, Gavin
Shen, Ben
Solt, Laura A
Su, Andrew
Wu, Chunlei
Ye, Li

Adjunct Faculty