Ricardo Dolmetsch

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Ricardo Dolmetsch
Born (1969-03-07) March 7, 1969 (age 55)
Cali, Colombia
NationalityColombia
Alma materBrown University
Known forRegulation of gene transcription by calcium signaling, lymphocyte activation, models of human disease using induced pluripotent stem cells, gene therapy
Scientific career
FieldsNeurobiology, calcium cell signaling
InstitutionsTempero Bio, Stanford University
Doctoral advisorRichard Lewis
Other academic advisorsMichael Greenberg

Ricardo Dolmetsch, born Richard Carl Elciario Dolmetsch; is a Colombian-American neuroscientist, Stanford University professor and biotechnology entrepreneur. He is known for his research on calcium signaling in neurons[1] and lymphocytes,[2] and for his work in neuropsychiatric disease.[3] He was an early developer of human stem cell models for studying diseases of the brain and heart, both in his laboratory at Stanford University and at the Allen Institute for Brain Science. As the Global Head of Neuroscience at Novartis, he helped create a drug pipeline for neuropsychiatric diseases,[4][5][6] introduced human stem cell models as tools for drug discovery in neuroscience[7][8] and contributed to the development of several treatments for brain disorders that are now in the clinic including Aimovig (Erenumab) for migraine and Kesimpta (Ofatumumab) for multiple sclerosis. Dolmetsch was also involved in early successes in gene therapy, including two approved therapies – Zolgensma (a cure for spinal muscular atrophy, sold by Novartis) and Hemgenix (the first gene therapy for hemophilia, made by uniQure and sold by CSL Limited). Dolmetsch is currently the President of Tempero Bio, a biotech company seeking to cure substance use disorders, and an Adjunct Professor in Neurobiology at Stanford University.

Biography and education

Dolmetsch was born and raised in Cali, Colombia and attended Colegio Bolivar. He was a member of the Colombian National Track team, winning the Colombian National Championships and representing his county in both the Pan American and Junior World Championships. Dolmetsch migrated to the United States to earn a Bachelor in Science from Brown University. He obtained a doctorate in Neuroscience from Stanford University in 1997 under the supervision of Richard Lewis,[9] where he worked on the role of calcium oscillations in lymphocyte activation[2][10] He completed a postdoctoral fellowship with Michael E. Greenberg at Harvard Medical School where he studied excitation-transcription coupling, specifically the role of voltage-gated calcium channels in controlling the activation of transcription factors in neurons.[1] His graduate and postdoctoral work established a role for intracellular calcium oscillation frequency and amplitude in regulating transcription in eukaryotic cells.

Career

Dolmetsch led a laboratory at Stanford University from 2002 to 2013 that studied the influence of electrical activity and calcium signals on early brain development.[11]

For two years he was also a Senior Director at the Allen Institute for Brain Science.[12] Early work in the Dolmetsch lab described some of the signaling pathways that connect L-type calcium channels to gene activation,[13] and identified the link between voltage gated calcium channels and store-operated calcium channels.[14] The lab developed technologies to study cell signaling, including light-activated signaling proteins to control biochemical cascades,[15] and induced pluripotent stem cell (iPSC)-based models of cardiac[16] and neuronal cells. His lab was one of the first to use neurons differentiated from human iPSCs to model neurodevelopmental and neuropsychiatric diseases, both at Stanford and at the Allen Institute for Brain Science.[3] His papers on Timothy Syndrome[17] and Phelan McDermid Syndrome[18] identified neuronal defects in induced pluripotent stem cells from patients, setting the stage for the use of these models for drug development.

In 2013, Dolmetsch accepted a position as the Global Head of Neuroscience at the Novartis Institute of Biological Research (NIBR).[3][8] At NIBR, he founded a research and early development team and curated a drug development pipeline that included treatments for rare orphan disorders, neurodegenerative diseases, calcium channelopathies and neuropsychiatric disorders such as autism, schizophrenia and addiction.[6][19] His group pioneered the use of human stem cell-derived cellular models[20] and genome-scale CRISPR screens[21][22] in neuroscience drug development[7] and invested in adeno-associated (AAV) gene therapies.[23] His team at NIBR helped bring several therapies to the clinic, including Erenumab (Aimovig) for migraine, Siponimod (Mayzent) and Ofatumumab (Kesimpta) for multiple sclerosis, and AVX001 (Zolgensma), the first gene therapy for SMA.[24]

After seven years at Novartis, Dolmetsch was appointed President of Research and Development at uniQure,[25] a company developing gene therapies for the liver and the central nervous system; he was later promoted to Chief Scientific Officer. Under his leadership uniQure built a broad gene therapy pipeline that included AMT-130, the first gene therapy for Huntington's disease, AMT260, the first gene therapy for temporal lobe epilepsy, and AMT-191, a treatment for Fabry. He also led uniQure's successful clinical testing and registration of Hemgenix, a cure for hemophilia that received FDA approval in 2022. Hemgenix received the 2023 Prix Galien USA Award in the category of Rare/Orphan Diseases.

Impact and awards

Dolmetsch has published over 70 scientific papers and received numerous awards for his research, including an Andrew Carnegie Prize in Mind and Brain Sciences,[26] the 2007 Society for Neuroscience Young Investigator Award,[11] a McKnight Foundation technology award in neuroscience and an NIH Director's Pioneer Award. While at Stanford he was named a Simons Foundation Autism Research Initiative investigator and a Barbara and John Packard Faculty Scholar. The gene therapy Hemgenix, which he helped shepherd into the clinic at uniQure, was awarded the 2023 Prix Galien Award for Best Product for Rare/Orphan Diseases.[27]

Dolmetsch has mentored many scientists that have gone on to successful careers in business and academia including Sergiu P. Pașca[28] Alexander Shcheglovitov, Chan-young Park, Jacob Brenner, Georgia Panagiotakos, Masayuki Yazawa, Eric Green, Natalia Gomez-Ospina, Ajamete Kaykas, Fiona Elwood,[29] Gopi Shankar, Rajeev Sivasankaran and Melvin Evers. He is currently the President of the clinical-stage biotechnology company Tempero Bio that is developing novel medicines to help patients recover from addiction. He is also an Adjunct Professor at Stanford University, where he teaches courses in neurobiology, biotechnology and drug development.

References

  1. ^ a b Dolmetsch RE, Pajvani U, Fife K, Spotts JM, Greenberg ME (Oct 12, 2001). "Signaling to the nucleus by an L-type calcium channel-calmodulin complex through the MAP kinase pathway". Science. 294 (5541): 333–9. Bibcode:2001Sci...294..333D. doi:10.1126/science.1063395. PMID 11598293. S2CID 2768067.
  2. ^ a b Dolmetsch RE, Lewis RS, Goodnow CC, Healy JI (April 24, 1997). "Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Erratum in: Nature 1997 Jul 17". Nature. 386 (6627): 855–8. doi:10.1038/386855a0. PMID 9126747. S2CID 4366554.
  3. ^ a b c Dreifus, Claudia (2014-03-24). "Seeking Autism's Biochemical Roots". The New York Times. Retrieved January 3, 2024.
  4. ^ Sangamo and Novartis partner on gene therapies for autism Ben Hargreaves. BioPharma Reporter 03-Aug-2020
  5. ^ Novartis and Sangamo partner on zinc finger therapies for autism and intellectual disability. Ryan Cross. Chemical and Engineering News, July 30 2020
  6. ^ a b Shining Light on Madness. David Rotman, MIT Technology Review. June 17, 2014
  7. ^ a b "Ricardo Dolmetsch". iBiology. iBiology Inc. Retrieved January 7, 2024.
  8. ^ a b Dolmetsch, R. (2013). "Straight talk with...Ricardo Dolmetsch". Nat Med. 19 (11): 1360. doi:10.1038/nm1113-1360. PMID 24202377.
  9. ^ "People – Alumni". Stanford Medicine. Stanford University. Retrieved January 8, 2024.
  10. ^ Dolmetsch RE, Xu K, Lewis RS (April 30, 1998). "Calcium oscillations increase the efficiency and specificity of gene expression". Nature. 392 (6679): 933–6. Bibcode:1998Natur.392..933D. doi:10.1038/31960. PMID 9582075. S2CID 205001579.
  11. ^ a b Poh, Alyssa (2018-04-08). "A young and slightly off-kilter scientist thrives". Stanford Medicine.
  12. ^ Gewin, V. (2012). "Turning point: Ricardo Dolmetsch". Nature. 485 (7399): 537. doi:10.1038/nj7399-537a.
  13. ^ Gomez-Ospina, N.; Panagiotakos, G.; Portmann, T.; Pasca, S.P.; Rabah, D.; Budzillo, A.; Kinet, J.P.; Dolmetsch, R.E. (2013-04-16). "A promoter in the coding region of the calcium channel gene CACNA1C generates the transcription factor CCAT". PLOS ONE. 8 (4): e60526. Bibcode:2013PLoSO...860526G. doi:10.1371/journal.pone.0060526. PMC 3628902. PMID 23613729.
  14. ^ Park, C.Y.; Shcheglovitov, A.; Dolmetsch, R. (2010-10-01). "The CRAC channel activator STIM1 binds and inhibits L-type voltage-gated calcium channels". Science. 330 (6000): 101–105. Bibcode:2010Sci...330..101P. doi:10.1126/science.1191027. PMID 20929812. S2CID 206527088.
  15. ^ Yazawa, M.; Sadaghiani, A.M.; Hsueh, B.; Dolmetsch, R.E. (2009-10-04). "Induction of protein-protein interactions in live cells using light". Nat Biotechnol. 27 (10): 941–945. doi:10.1038/nbt.1569. PMID 19801976. S2CID 205274357.
  16. ^ Yazawa, M.; Hsueh, B.; Jia, X.; Pasca, A. M.; Bernstein, J. A.; Hallmayer, J.; Dolmetsch, R. E. (2011-03-10). "Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome". Nature. 471 (7337): 230–234. Bibcode:2011Natur.471..230Y. doi:10.1038/nature09855. PMC 3077925. PMID 21307850.
  17. ^ Paşca, S.P.; Portmann, T.; Voineagu, I.; Yazawa, M.; Shcheglovitov, A.; Paşca, A.M.; Cord, B.; Palmer, T.D.; Chikahisa, S.; Nishino, S.; Bernstein, J.A.; Hallmayer, J.; Geschwind, D.H.; Dolmetsch, R.E. (2011-11-27). "Using iPSC-derived neurons to uncover cellular phenotypes associated with Timothy syndrome". Nat Med. 17 (12): 1657–1662. doi:10.1038/nm.2576. PMC 3517299. PMID 22120178.
  18. ^ Shcheglovitov, A.; Shcheglovitova, O.; Yazawa, M.; Portmann, T.; Shu, R.; Sebastiano, V.; Krawisz, A.; Froehlich, W.; Bernstein, J.A.; Hallmayer, J.F.; Dolmetsch, R.E. (2013-11-14). "SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients". Nature. 503 (7475): 267–271. Bibcode:2013Natur.503..267S. doi:10.1038/nature12618. PMC 5559273. PMID 24132240.|
  19. ^ Branca M (May 2021). "Slivers of the spectrum". Nat Biotechnol. 39 (5): 540–545. doi:10.1038/s41587-021-00913-8. PMC 8061880. PMID 33888895.
  20. ^ Sun Y, Dolmetsch RE (Jan 11, 2016). "How induced pluripotent stem cells are informing drug discovery in psychiatry". Swiss Med Wkly. 146 (w14241): w14241. doi:10.4414/smw.2016.14241. PMID 26752334.
  21. ^ Ihry, R.J.; Worringer, K.A.; Salick, M.R.; Frias, E.; Ho, D.; Theriault, K.; Kommineni, S.; Chen, J.; Sondey, M.; Ye, C.; Randhawa, R.; Kulkarni, T.; Yang, Z.; McAllister, G.; Russ, C.; Reece-Hoyes, J.; Forrester, W.; Hoffman, G.R.; Dolmetsch, R.; Kaykas, A. (July 2018). "p53 inhibits CRISPR-Cas9 engineering in human pluripotent stem cells". Nat Med. 24 (7): 939–946. doi:10.1038/s41591-018-0050-6. PMID 29892062.
  22. ^ Ihry, R.J.; Salick, M.R.; Ho, D.J.; Sondey, M.; Kommineni, S.; Paula, S.; Raymond, J.; Henry, B.; Frias, E.; Wang, Q.; Worringer, K.A.; Ye, C.; Russ, C.; Reece-Hoyes, J.S.; Altshuler, R.C.; Randhawa, R.; Yang, Z.; McAllister, G.; Hoffman, G.R.; Dolmetsch, R.; Kaykas, A. (2019-04-09). "Genome-Scale CRISPR Screens Identify Human Pluripotency-Specific Genes". Cell Rep. 27 (2): 616–630.e6. doi:10.1016/j.celrep.2019.03.043. PMID 30970262.
  23. ^ Sabatino DE, Bushman FD, Chandler RJ, Crystal RG, Davidson BL, Dolmetsch R, Eggan KC, Gao G, Gil-Farina I, Kay MA, McCarty DM, Montini E, Ndu A, Yuan J (Aug 3, 2022). "American Society of Gene and Cell Therapy (ASGCT) Working Group on AAV Integration. Evaluating the state of the science for adeno-associated virus integration: An integrated perspective". Mol Ther. 30 (8): 2646–2663. doi:10.1016/j.ymthe.2022.06.004. PMC 9372310. PMID 35690906.
  24. ^ AveXis receives FDA approval for Zolgensma, the first and only gene therapy for pediatric patients with spinal muscular atrophy (SMA), Novartis Press Release May 14,2019
  25. ^ uniQure Announces Appointment of Ricardo Dolmetsch, PhD, as President, Research & Development. Yahoo! Finance August 26, 2020
  26. ^ "Press Release: Carnegie Mellon To Present Ricardo Dolmetsch with Andrew Carnegie Prize in Mind and Brain Sciences". Carnegie Mellon University. 2014-04-07. Retrieved January 2, 2024.
  27. ^ Buntz, Brian (2023-11-01). "Prix Galien Awards: The most innovative biotech, pharma, and orphan drugs of 2023". Drug Discovery and Development. Retrieved January 3, 2024.
  28. ^ Khan, T.A.; Revah, O.; Gordon, A.; Yoon, S.J.; Krawisz, A.K.; Goold, C.; Sun, Y.; Kim, C.H.; Tian, Y.; Li, M.Y.; Schaepe, J.M.; Ikeda, K.; Amin, N.D.; Sakai, N.; Yazawa, M.; Kushan, L.; Nishino, S.; Porteus, M.H.; Rapoport, J.L.; Bernstein, J.A.; O'Hara, R.; Bearden, C.E.; Hallmayer, J.F.; Huguenard, J.R.; Geschwind, D.H.; Dolmetsch, R.E.; Paşca, S.P. (Dec 2020). "Neuronal defects in a human cellular model of 22q11.2 deletion syndrome". Nat Med. 26 (12): 1888–1898. doi:10.1038/s41591-020-1043-9. PMC 8525897. PMID 32989314.
  29. ^ "Woman of the Week: Janssen's Fiona Elwood". PharmaVoice. Retrieved January 7, 2024.
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