Technology

Approach

The central nervous system (CNS) contains both excitatory cells (primarily neurons that express glutamate) and inhibitory cells (primarily neurons that express GABA). Normal brain and spinal cord function depends on a delicate balance between these two types of neurons. This balance is normally established during embryonic development and just after birth when the nervous system is still assembling and developing neurologic connections. During this time, neurons are born, migrate to proper locations, and form connections or synapses, creating complex circuits that are maintained into adulthood. Problems arise when genetic mutations and/or external traumas result in aberrant development and/or degeneration of particular CNS cell types, leading to the dysregulation of neural circuits. Epileptic seizures, neuropathic pain, spasticity, and certain types of cognitive impairments and psychoses can be symptomatic of dysregulated neural activity. Because the genesis of new neurons and synapses, or plasticity, is limited in the adult CNS, these diseases persist and lack effective treatment. Notably, effective drugs are lacking for many patients with neuropathic pain, and one-third of epilepsy patients do not respond to current anti-epileptic drugs.

Neurona’s founders have discovered that transplantation of specialized neurons in the adult CNS can rebalance neural activity and induce plasticity to repair neural circuits. Neurona is using human stem cell technologies to develop novel cell-based therapeutics.

 

Scientific Publications

Selected Founders’ Publications:
  • Fandel T. M., Trivedi A., Nicholas C. R., Zhang H., Chen J., Martinez A.F., Noble-Haeusslein L. J., Kriegstein A. R. (2016). Transplanted Human Stem Cell-Derived Interneuron Precursors Mitigate Mouse Bladder Dysfunction and Central Neuropathic Pain after Spinal Cord Injury, Cell Stem Cell, In Press doi: 10.1016/j.stem.2016.08.020. Epub 2016 Sept 22 more ⇨
  • Harwell C. C., Fuentealba L. C., Gonzalez-Cerrillo A., Parker P. R., Gertz C. C., Mazzola E., Garcia M. T., Alvarez-Buylla A., Cepko C. L., Kriegstein A. R. (2015). Wide Dispersion and Diversity of Clonally Related Inhibitory Interneurons. Neuron. Sep 2;87(5):999-1007. doi: 10.1016/j.neuron.2015.07.030. Epub 2015 Aug 20 more ⇨
  • Vogt D, Cho KK, Lee AT, Sohal VS, Rubenstein JL. (2015). The parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles. Cell Rep, 11(6):944-56. doi: 10.1016/j.celrep.2015.04.019 more ⇨
  • Bráz JM, Wang X, Guan Z, Rubenstein JL, Basbaum AI. (2015). Transplant-mediated enhancement of spinal cord GABAergic inhibition reverses paclitaxel-induced mechanical and heat hypersensitivity. Pain, 156(6):1084-91 more ⇨
  • Vogt D., Wu P. R., Sorrells S. F., Arnold C., Alvarez-Buylla A., Rubenstein J. L. R. (2015). Viral-mediated Labeling and Transplantation of Medial Ganglionic Eminence (MGE) Cells for In Vivo Studies. J. Vis. Exp. (98), e52740, doi:10.3791/52740 more ⇨
  • Fu Y, Kaneko M, Tang Y, Alvarez-Buylla A, Stryker MP. (2015). A cortical disinhibitory circuit for enhancing adult plasticity. Elife. 4:e05558. doi: 10.7554/eLife.05558 more ⇨
  • Tang Y, Stryker MP, Alvarez-Buylla A, Espinosa JS. (2014). Cortical plasticity induced by transplantation of embryonic somatostatin or parvalbumin interneurons. Proc Natl Acad Sci, 111(51):18339-44. doi: 10.1073/pnas.1421844112 more ⇨
  • Southwell D. G., Nicholas C. R., Basbaum A. I., Stryker M. P., Kriegstein A. R., Rubenstein J. L., Alvarez-Buylla A. (2014). Interneurons from Embryonic Development to Cell-Based Therapy. Science, 344(6180), 1240622. doi:10.1126/science.1240622 more ⇨
  • Vogt D, Hunt RF, Mandal S, Sandberg M, Silberberg SN, Nagasawa T, Yang Z, Baraban SC, Rubenstein JL. (2014). Lhx6 directly regulates Arx and CXCR7 to determine cortical interneuron fate and laminar position. Neuron, 82(2):350-64 more ⇨
  • Sebe J. Y., Looke-Stewart E., Dinday M. T., Alvarez-Buylla A., Baraban S. C. (2014). Neocortical integration of transplanted GABA progenitor cells from wild type and GABAB receptor knockout mouse donors. Neuroscience Letters, 561, 52–57. doi:10.1016/j.neulet.2013.11.012 more ⇨
  • Merkle F. T., Fuentealba L. C., Sanders T. A., Magno L., Kessaris, N., Alvarez-Buylla, A. (2014). Adult neural stem cells in distinct microdomains generate previously unknown interneuron types. Nature Neuroscience, 17(2), 207–214. doi:10.1038/nn.3610 more ⇨
  • Tong L. M., Djukic B., Arnold C., Gillespie A. K., Yoon S. Y., Wang M. M., Zhang O., Knoferle J., Rubenstein J. L., Alvarez-Buylla A., Huang Y. (2014). Inhibitory Interneuron Progenitor Transplantation Restores Normal Learning and Memory in ApoE4 Knock-In Mice without or with Aβ Accumulation. The Journal of Neuroscience, 34(29), 9506–9515. doi:10.1523/JNEUROSCI.0693-14.2014 more ⇨
  • Hansen D. V. Lui, J. H., Flandin P., Yoshikawa K., Rubenstein J. L., Alvarez-Buylla A., Kriegstein A. R. (2013). Non-epithelial stem cells and cortical interneuron production in the human ganglionic eminences. Nature Neuroscience, 16(11), 1576–1587. doi:10.1038/nn.3541 more ⇨
  • Chen Y-J. J., Vogt D., Wang Y., Visel A., Silberberg S. N., Nicholas C. R., Danjo T., Pollack J. L., Pennacchio L. A., Anderson S. (2013). Use of “MGE Enhancers” for Labeling and Selection of Embryonic Stem Cell-Derived Medial Ganglionic Eminence (MGE) Progenitors and Neurons. PLoS ONE 8(5): e61956. doi:10.1371/journal.pone.0061956 more ⇨
  • Hunt R. F., Girskis K. M., Rubenstein J. L., Alvarez–Buylla A., Baraban, S. C. (2013). GABA progenitors grafted into the adult epileptic brain control seizures and abnormal behavior. Nature Neuroscience, 16(6), 10.1038/nn.3392. doi:10.1038/nn.3392 more ⇨
  • Nicholas C. R., Chen J., Tang Y., Southwell D. G., Chalmers N., Vogt D., Arnold C. M., Chen Y-J. J., Stanley E. G., Elefanty A. G., Sasai Y., Alvarez-Buylla A., Rubenstein J. L., Kriegstein A. R. (2013). Functional maturation of hPSC-derived forebrain interneurons requires an extended timeline and mimics human neural development. Cell Stem Cell, 12(5), 573–586. doi:10.1016/j.stem.2013.04.005 more ⇨
  • Bráz J., Sharif-Naeini R., Vogt D., Kriegstein A., Alvarez-Buylla A., Rubenstein J., Basbaum A. (2012). Forebrain GABAergic neuron precursors integrate into adult spinal cord and reduce injury-induced neuropathic pain. Neuron, 74(4), 663–675. doi:10.1016/j.neuron.2012.02.033 more ⇨
  • Southwell DG, Paredes MF, Galvao RP, Jones DL, Froemke RC, Sebe JY, Alfaro-Cervello C, Tang Y, Garcia-Verdugo JM, Rubenstein JL, Baraban SC, Alvarez-Buylla A. (2012). Intrinsically determined cell death of developing cortical interneurons. Nature, 491(7422):109-13. doi: 10.1038/nature11523 more ⇨
  • Martínez-Cerdeño V., Noctor S. C., Espinosa A., Ariza J., Parker P., Orasji S., Daadi M. M., Bankiewicz K., Alvarez-Buylla A., Kriegstein, A. R. (2010). Embryonic MGE Precursor Cells Grafted into Adult Rat Striatum Integrate and Ameliorate Motor Symptoms in 6-OHDA-Lesioned Rats. Cell Stem Cell, 6(3), 238–250. doi:10.1016/j.stem.2010.01.004 more ⇨
  • Southwell DG, Froemke RC, Alvarez-Buylla A, Stryker MP, Gandhi SP. (2010). Cortical plasticity induced by inhibitory neuron transplantation. Science, 327(5969):1145-8. doi: 10.1126/science.1183962 more ⇨
  • Baraban S. C., Southwell D. G., Estrada R. C., Jones D. L., Sebe J. Y., Alfaro-Cervello C, García-Verdugo, J. M., Rubenstein J. L. R., and Alvarez-Buylla A., Reduction of seizures by transplantation of cortical GABAergic interneuron precursors into Kv1.1 mutant mice. (2009) PNAS 106 (36) 15472-15477. doi:10.1073/pnas.0900141106 more ⇨
  • Alvarez-Dolado M, Calcagnotto ME, Karkar KM, Southwell DG, Jones-Davis DM, Estrada RC, Rubenstein JL, Alvarez-Buylla A, Baraban SC. (2006). Cortical inhibition modified by embryonic neural precursors grafted into the postnatal brain. J Neurosci, 26(28):7380-9 more ⇨
  • Cobos I., Calcagnotto M. E., Vilaythong A. J., Thwin M. T., Noebels J. L., Baraban S. C., Rubenstein J. L. R. (2005). Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy, Nature Neuroscience 8, 1059 – 1068 more ⇨
  • Wichterle H, Turnbull DH, Nery S, Fishell G, Alvarez-Buylla A. (2001). In utero fate mapping reveals distinct migratory pathways and fates of neurons born in the mammalian basal forebrain. Development, 128(19):3759-71 more ⇨
  • Anderson SA, Marín O, Horn C, Jennings K, Rubenstein JL. (2001). Distinct cortical migrations from the medial and lateral ganglionic eminences. Development, 128(3):353-63 more ⇨
  • Wichterle H, Garcia-Verdugo JM, Herrera DG, Alvarez-Buylla A. (1999). Young neurons from medial ganglionic eminence disperse in adult and embryonic brain. Nat Neurosci, 2(5):461-6 more ⇨
  • Sussel L, Marin O, Kimura S, Rubenstein JL. (1999). Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum. Development, 126(15):3359-70 more ⇨
  • Anderson SA, Eisenstat DD, Shi L, Rubenstein JL. (1997). Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes. Science, 278(5337):474-6 more ⇨