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Methods for Identifying Agent and Conditions That Modulate Neurogenesis

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(19) & (11) EP 2 317 316 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 04.05.2011 Bulletin 2011/18 G01N 33/50 (2006.01) G01N 33/94 (2006.01) (21) Application number: 10015900.3 (22) Date of filing: 07.07.2006 (84) Designated Contracting States: • Pires, Jammieson AT BE BG CH CY CZ DE DK EE ES FI FR GB GR San Diego, California 92139 (US) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • Lorrain, Kym I. SK TR San Diego, California 92124 (US) • Carter, Todd (30) Priority: 08.07.2005 US 697905 P San Diego, California 92129 (US) 31.01.2006 US 763883 P • Treuner, Kai San Diego, California 92122 (US) (62) Document number(s) of the earlier application(s) in accordance with Art. 76 EPC: (74) Representative: Roques, Sarah Elizabeth 06800028.0 / 1 904 843 J.A. Kemp & Co. 14 South Square (71) Applicant: Braincells, Inc. Gray’s Inn San Diego, CA 92121 (US) London WC1R 5JJ (GB) (72) Inventors: Remarks: • Barlow, Carrolee This application was filed on 21-12-2010 as a Del Mar, California 92014 (US) divisional application to the application mentioned under INID code 62. (54) Methods for identifying agent and conditions that modulate neurogenesis (57) Methods and tools for identifying agents and conditions that modulate neurogenesis are disclosed. The disclo- sure also relates to methods and tools for identifying populations of neural stem cells suitable for transplantation. EP 2 317 316 A2 Printed by Jouve, 75001 PARIS (FR) 1 EP 2 317 316 A2 2 Description pear when up to 70% of TH- positive nigrostriatal neurons have degenerated. Surgical therapies aimed at replacing CROSS-REFERENCES TO RELATED APPLICATIONS lost dopaminergic neurons or disrupting aberrant basal ganglia circuitry have recently been tested (C. Honey et [0001] This application claims benefit of priority under 5 al. 1999), but the primary goal of forestalling disease pro- 35 U.S.C. § 119(e) from U.S. Provisional Patent Appli- gression in newly diagnosed patients has yet to be real- cations 60/697,905, filed July 8, 2005, and 60/763,883, ized. Thus, there are currently no satisfactory methods filed January 31, 2006, both of which are hereby incor- for curing, preventing or treating Parkinson’s disease or porated by reference as if fally set forth. its symptoms. However, considering the role of neuro- 10 degeneration in Parkinson’s disease, neurogenesis- FIELD OF THE DISCLOSED INVENTION based treatments provide a means for directly treating the underlying cause of the disease. [0002] The disclosed invention relates to methods and [0005] Agents that modulate neurogenesis also hold tools for identifying agents and conditions that modulate promise for the treatment of depression and other mood neurogenesis. Moreover, the disclosed invention relates 15 disorders. For example, neurogenesis is thought to play to methods and compositions relating to the ex vivo prep- an important homeostatic role in the hippocampus of de- aration of neural cells for transplantation into a subject. pressed patients. Pathological stimuli, such as depres- The disclosed invention also relates to methods and tools sion, can cause neuronal atrophy and death, which leads for identifying populations of neural stem cells suitable to a reduction in hippocampal volume that is correlated for transplantation. 20 with the length and severity of the depression. Antide- pressant medications have been reported as able to re- BACKGROUND verse the reduction in hippocampal volume. Known anti- depressants have been reported in animal models as [0003] Neurogenesis is a vital process in the brains of exhibiting such a stimulatory effect, and genetic models animals and humans, whereby new nerve cells are con- 25 suggest that hippocampal neurogenesis may be required tinuously generated throughout the life span of the or- for antidepressant activity. For example, neurogenesis ganism. The newly generated cells are able to differen- has been reported pre-clinically to be required for the tiate into functional cells of the central nervous system antidepressant efficacy of Prozac and other antidepres- and integrate into existing neural circuits in the brain. sant drugs (Santarelli, Saxe et al. 2003). Moreover, the Neurogenesis persists throughout adulthood in two re- 30 time required for the therapeutic onset of action of anti- stricted regions of the mammalian brain: the subventricu- depressants has been reported to correlate with the time lar zone (SVZ) of the lateral ventricles and the dentate course of neurogenesis. Thus, evidence suggests that gyrus of the hippocampus. In these regions, multipotent the ability of currently available antidepressant medica- neural progenitor cells (NPCs) continue todivide and give tions to treat depression is at least partly due to their rise to new functional neurons and glial cells (for review 35 neurogenesis-stimulating properties. Gage 2000). It has been shown that a variety of factors [0006] Despite their effects on neurogenesis, most can stimulate adult hippocampal neurogenesis, e.g. currently available antidepressants were primarily devel- adrenalectomy, voluntary exercise, enriched environ- oped to modulate other processes. For example, most ment,hippocampus dependent learning andanti- depres- medications target specific receptor systems that partic- sants (Yehuda 1989, van Praag 1999, Brown J 2003, 40 ipate in complex signaling networks and are multifunc- Gould 1999, Malberg 2000, Santarelli 2003). Other fac- tional. As a result, most medications have non-specific tors, such as adrenal hormones, stress, age and drugs mechanisms of action that can lead to undesirable side of abuse negatively influence neurogenesis (Cameron effects and reduced efficacy. For example, leading anti- 1994, McEwen 1999, Kuhn 1996, Eisch 2004). depressants (i.e., the SSRIs) are plagued by significant [0004] Drugs with the potential to modulate neurogen- 45 sexual (decreased libido and delayed ejaculation), GI esis hold great promise as therapeutic agents against (nausea) and central nervous system (headache) side many diseases-including, but not limited to, Alzheimer’s effects in at least 10% of the treatment population, and disease, Parkinson’s disease, traumatic brain injury, de- often require 4-6 weeks before onset of action. In addi- velopmental disorders, depression and mood disorders, tion, 30-40% of patients with depression do not respond stroke, and epilepsy. For example, Parkinson’s disease 50 to treatment with oral antidepressants. Thus, the identi- is a progressive neurodegenerative disorder character- fication of agents that specifically target neurogenesis ized by the loss of the nigrostriatal pathway as a result provides opportunities for the development of more spe- of degeneration of dopaminergic neurons within the sub- cific and efficacious treatments for depression by avoid- stantia nigra. Although the cause of Parkinson’s disease ing the receptors and pathways associated with the side is not known, it is associated with the progressive death 55 effects of current antidepressants. of dopaminergic (tyrosine hydroxylase (TH) positive) [0007] Neurogenesis-based treatments may also be mesencephalic neurons, inducing motor impairment. effective in treating the cognitive decline associated with The characteristic symptoms of Parkinson’s disease ap- irradiation or chemotherapy treatments of a primary or 2 3 EP 2 317 316 A2 4 metastatic brain tumor. Such declines occur in ∼50% of vention provide tools with increased sensitivity, specifi- patients, but there are currently few successful treat- city and predictive value for detecting the effect of a wide ments or preventive strategies. In animal models, radia- range of treatment modalities on neurogenesis. In some tion-induced brain injury is thought to be caused by hip- embodiments, a method of the disclosed invention is pocampal dysfunction resulting from decreased neuro- 5 used to develop improved antidepressants by identifying genesis (Monje et al., 2002). Radiation induces a defect molecules or other treatments that modulate key steps in the proliferative capacity of the neural progenitor cell in the neurogenesis cascade. The improved antidepres- population, while the remaining neural precursors adopt sants include those that exhibit enhanced efficacy in the a non-neuronal glial fate. When grafted stem/precursor treatment of depression and related mood disorders rel- cells are implanted into radiated animal hippocampus 10 ative to currently available medications. there is a marked reduction in the differentiation of these [0012] Aspects of the disclosed invention include as- cells into neurons, indicating that the microenvironment says for neurosphere growth (or proliferation), which may impacts neurogenesis. Radiation results in a marked in- be embodied in a quantifiable and/or high throughput crease in the number of activated microglia which secrete method, and an assay based on neural cells in monol- cytokinesthat influence neural precursor cell proliferation 15 ayer, or adherent, form as opposed to non-adherent neu- and fate (Monje et al., 2002). For example, microglia se- rospheres in suspension. crete interleukin (IL)-6, which has been shown to de- [0013] Thus in a first aspect, a method for identifying crease in vitro neurogenesis, cell survival, and accumu- and characterizing neural stem cells in cell culture known lation of neurons, likely due to reduced neuronal differ- as the neurosphere assay (NSA) is described herein. In entiation (Monje et al., 2003). Thus, IL-6 is a potent reg- 20 the NSA, cells isolated
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