Author: David P Soskin
Proposal Summary: Investigation of ARA 290 (CNS targeted Erythropoietin) as a Novel Therapeutic Agent in Major Depressive Disorder
I. Background
Major depressive disorder (MDD) has the highest lifetime prevalence rate of any psychiatric disorder (Kessler et al., 2005), and is associated with significant medical co-morbidity and functional disability (Kessler et al., 2003). Current pharmacological treatments are considered to be suboptimal (American Psychiatric Association, 2000): only approximately 50% of outpatients starting treatment with a selective serotonin reuptake inhibitor (SSRI) will respond (Agency for Health Care Policy and Research, 1993) and fewer will remit (Trivedi et al., 2006). Perhaps more problematic, between 40% and 60% of responders will relapse within one year (Ramana et al., 1995; Rush et al., 2006). Given the limited efficacy of existing treatments and the historical decline in the development of antidepressants (Shorter & Tyrer, 2003), there is increasing clinical urgency to develop novel agents.
Erythropoietin
Erythropoietin (EPO) is a 165 amino acid (30 kDa) glycoprotein, which regulates the production of red blood cells (M. Brines & Cerami, 2005). Surprisingly, EPO was also recently discovered to be a member of the type I cytokine superfamily (Anagnostou, Lee, Kessimian, Levinson, & Steiner, 1990). In addition to being produced by the kidneys, EPO is synthesized by neurons, astrocytes, and endothelial cells in the brain, and helps to modulate neurodevelopment, adult neurogenesis, and neuroprotection (Miskowiak, Vinberg, Harmer, Ehrenreich, & Kessing, 2012).
These central nervous system (CNS) properties have yielded novel therapeutic uses. In high doses (>500 IU/kg body weight), systemically administered EPO crosses the blood-brain barrier (M. L. Brines et al., 2000), and has neuroprotective and neurotrophic effects in traumatic, ischemic, excitotoxic, and inflammatory brain damage (M. L. Brines et al., 2000; Morishita, Masuda, Nagao, Yasuda, & Sasaki, 1997; Sakanaka et al., 1998) and neurodegenerative and neuropsychiatric conditions (Agnello et al., 2002; Li et al., 2004; Sattler et al., 2004; Siren et al., 2006). Additionally, EPO exerts pro-cognitive effects in acute and chronic neural injury models, including embolic stroke (Ding et al., 2010), closed head injury (Yatsiv et al., 2005), spinal cord injury (Boran, Colak, & Kutlay, 2005), schizophrenia (Ehrenreich et al., 2004), and chronic progressive multiple sclerosis (Bartels, Spate, Krampe, & Ehrenreich, 2008; Siren, Fasshauer, Bartels, & Ehrenreich, 2009).
There is now a substantial body of literature indicating that EPO has antidepressant effects. In a recent review, Wikowiak et al. found that 4 of the 5 animal studies (Adamcio et al., 2008; Girgenti et al., 2009; Leconte et al., 2011; Miu, Olteanu, Chis, & Heilman, 2004; Mogensen et al., 2004) and 6 human proof-of-concept studies (4 in healthy volunteers and 2 in depressed patients) demonstrated beneficial effects on hippocampus-dependent memory and antidepressant-like effects (Miskowiak et al., 2012). In depressed patients, 2 placebo-controlled trials have found changes in emotional auto-appraisal consistent with an antidepressant mechanism (Miskowiak et al., 2009; Miskowiak et al., 2010). A phase 2 double-blind, randomized controlled trial of EPO for the treatment of patients with bipolar depression is currently recruiting patients; the study is expected to be completed in 2013 (Rigshospitalet; Denmark. The Effects of Erythropoietin on Depressive Symptoms and Neurocognitive Deficits in Patients With Treatment Resistant Depression and in Patients With Remitted Bipolar Disorder - a Proof of Concept Study. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2012- [cited 2012 Aug 27]. Available from: http://clinicaltrials.gov/show/NCT00916552 NLM Identifier: NCT00916552.)
II. Biological Rationale
Over the past decade, as we have learned more about EPO’s diverse functions in the CNS, there has also been a fundamental re-conception of major depressive disorder, as a CNS process involving excess activation of pro-inflammatory cytokines and dysregulation of neural plasticity. Pro-inflammatory cytokines, including interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) have been shown to be increased in individuals with MDD compared to healthy controls (Mossner et al., 2007; N. M. Simon et al., 2008; Zorrilla et al., 2001). In animal models, administration of pro-inflammatory cytokines or cytokine inducers have been associated with depression-like behavioral changes, including increased immobility time on the forced swim test, anhedonia, sleep disruption, and anorexia (Miller, Maletic, & Raison, 2009). These symptoms can be reversed through acute treatment with an anti-inflammatory cytokine (IL-10) or cytokine antagonist (IL-1RA), or chronic treatment with a serotonergic antidepressant (Dantzer, O'Connor, Freund, Johnson, & Kelley, 2008).
In humans, similar links between cytokine activity and mood changes have been established. Within the CNS, pro-inflammatory cytokines have been shown to modulate neurotransmitter systems, neurotrophic factors, and neurocircuitry associated with mood regulation. Approximately 20% to 50% of patients treated with the pro-inflammatory cytokine, interferon-alpha, for hepatits C or malignant melanoma will develop a clinical depression (Miller et al., 2009), and these rates can be dramatically reduced (approximately fourfold) following pre-treatment with the antidepressant, paroxetine (Musselman et al., 2001). In a study of patients with psoriasis, Tyring and colleagues found that individuals randomized to treatment with the TNF-alpha antagonist, etanercept, had significantly greater improvements in depressive symptoms (measured by the HAM-D-17) compared to controls; changes in core features of depression were only weakly correlated with objective measures of skin clearance and joint pain (Tyring et al., 2006). In a proof-of-concept study, Muller and colleagues found that depressed patients randomized to treatment with reboxetine combined with the COX-2 inhibitor, celecoxib, showed greater improvements in depression (measured by the HAM-D-17) compared to controls treated with reboxetine alone (Muller et al., 2006).
There is also now a substantial literature linking neurotrophic factors to the pathophysiology and treatment of major depressive disorder. In animal models, BDNF signaling in the hippocampus decreases under chronic stress conditions, and increases following ECT, or sustained treatment with several pharmacodynamically distinct antidepressants (SSRIs, NERIs, MAOIs) (Duman & Monteggia, 2006). Additionally, direct infusion of BDNF into the rodent hippocampus has been shown to induce neurogenesis and produce antidepressant-like effects (Santarelli et al., 2003; Shirayama, Chen, Nakagawa, Russell, & Duman, 2002) In a particularly exciting study, Tfilin and colleagues demonstrated that intracerebral infusion of mesechemyal stem cells also resulted in differentiation of new hippocampal neurons, and reduced behavioral measures of depression, such as immobility time on the the forced swim test (Tfilin et al., 2010). Currently, there are several neurotrophic agents in development for the treatment of depression. Inhibitors of phosphodiesterase 4 and 5 activate the cAMP system, and increase hippocampal BDNF expression (Fujimaki, Morinobu, & Duman, 2000). Rolpiram, a non-selective PDE-4 inhibitor, has been reported to reduce depressive symptoms in open (Zeller, Stief, Pflug, & Sastre-y-Hernandez, 1984) and controlled trials (Bertolino et al., 1988; Bobon et al., 1988; Fleischhacker et al., 1992).
ARA 290
Given EPO's anti-inflammatory and neurotrophic effects, both of which represent salient mechanisms of action for the treatment of MDD, and given empirical data that EPO has positive mood effects in healthy and depressed subjects, there is reason to believe it may represent a novel therapy for patients with treatment-resistant MDD. However, because EPO stimulates erythropoiesis, it also increases the risk of thromboembolic complications, hypertension and potentially malignant tumor growth (Jelkmann, Bohlius, Hallek, & Sytkowski, 2008; Miskowiak, Vinberg, Harmer, Ehrenreich, & Kessing, 2011). Therefore, a safer derivative of EPO, ARA 290, has recently been engineered.
ARA 290 is an 11-amino-acid EPO-derived peptide, which is non-erythropoietic, but retains therapeutic CNS properties. In animal models, ARA 290 has been shown to have CNS tissue protective properties (M. Brines & Cerami, 2008); decrease pro-inflammatory cytokines (McVicar et al., 2011); exert pro-cognitive effects (M. Brines et al., 2008); prevent programmed neuronal cell death (McVicar et al., 2011); and possibly promote neurogenesis (M. Brines et al., 2008). In humans, clinical trials are currently underway or in planning to evaluate its effect on neuropathy, rheumatoid arthritis, and cognition (http://araim.org/page-4/).
Summary and Significance
EPO is a highly promising, novel agent for the treatment of MDD. However, EPO’s side effect profile and burden of administration (e.g. high-dose IV infusions with weekly blood monitoring) will likely limit its clinical utility. In contrast, ARA 290 exhibits comparable efficacy for neural protection; target-engagement of EPO’s putative antidepressant mechanisms; and absence of serious side effects related to erythropoietic activity. No clinical trials have yet investigated ARA 290’s mood properties.
III. Potential collaborations
An academic institution could conduct any of the following studies to investigate additional mood-related indications for ARA 290 (including MDD, treatment-resistant MDD, post-stroke depression, and MDD co-morbid with chronic pain):
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Proposal Summary: Investigation of ARA 290 (CNS targeted Erythropoietin) as a Novel Therapeutic Agent in Major Depressive Disorder
I. Background
Major depressive disorder (MDD) has the highest lifetime prevalence rate of any psychiatric disorder (Kessler et al., 2005), and is associated with significant medical co-morbidity and functional disability (Kessler et al., 2003). Current pharmacological treatments are considered to be suboptimal (American Psychiatric Association, 2000): only approximately 50% of outpatients starting treatment with a selective serotonin reuptake inhibitor (SSRI) will respond (Agency for Health Care Policy and Research, 1993) and fewer will remit (Trivedi et al., 2006). Perhaps more problematic, between 40% and 60% of responders will relapse within one year (Ramana et al., 1995; Rush et al., 2006). Given the limited efficacy of existing treatments and the historical decline in the development of antidepressants (Shorter & Tyrer, 2003), there is increasing clinical urgency to develop novel agents.
Erythropoietin
Erythropoietin (EPO) is a 165 amino acid (30 kDa) glycoprotein, which regulates the production of red blood cells (M. Brines & Cerami, 2005). Surprisingly, EPO was also recently discovered to be a member of the type I cytokine superfamily (Anagnostou, Lee, Kessimian, Levinson, & Steiner, 1990). In addition to being produced by the kidneys, EPO is synthesized by neurons, astrocytes, and endothelial cells in the brain, and helps to modulate neurodevelopment, adult neurogenesis, and neuroprotection (Miskowiak, Vinberg, Harmer, Ehrenreich, & Kessing, 2012).
These central nervous system (CNS) properties have yielded novel therapeutic uses. In high doses (>500 IU/kg body weight), systemically administered EPO crosses the blood-brain barrier (M. L. Brines et al., 2000), and has neuroprotective and neurotrophic effects in traumatic, ischemic, excitotoxic, and inflammatory brain damage (M. L. Brines et al., 2000; Morishita, Masuda, Nagao, Yasuda, & Sasaki, 1997; Sakanaka et al., 1998) and neurodegenerative and neuropsychiatric conditions (Agnello et al., 2002; Li et al., 2004; Sattler et al., 2004; Siren et al., 2006). Additionally, EPO exerts pro-cognitive effects in acute and chronic neural injury models, including embolic stroke (Ding et al., 2010), closed head injury (Yatsiv et al., 2005), spinal cord injury (Boran, Colak, & Kutlay, 2005), schizophrenia (Ehrenreich et al., 2004), and chronic progressive multiple sclerosis (Bartels, Spate, Krampe, & Ehrenreich, 2008; Siren, Fasshauer, Bartels, & Ehrenreich, 2009).
There is now a substantial body of literature indicating that EPO has antidepressant effects. In a recent review, Wikowiak et al. found that 4 of the 5 animal studies (Adamcio et al., 2008; Girgenti et al., 2009; Leconte et al., 2011; Miu, Olteanu, Chis, & Heilman, 2004; Mogensen et al., 2004) and 6 human proof-of-concept studies (4 in healthy volunteers and 2 in depressed patients) demonstrated beneficial effects on hippocampus-dependent memory and antidepressant-like effects (Miskowiak et al., 2012). In depressed patients, 2 placebo-controlled trials have found changes in emotional auto-appraisal consistent with an antidepressant mechanism (Miskowiak et al., 2009; Miskowiak et al., 2010). A phase 2 double-blind, randomized controlled trial of EPO for the treatment of patients with bipolar depression is currently recruiting patients; the study is expected to be completed in 2013 (Rigshospitalet; Denmark. The Effects of Erythropoietin on Depressive Symptoms and Neurocognitive Deficits in Patients With Treatment Resistant Depression and in Patients With Remitted Bipolar Disorder - a Proof of Concept Study. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2012- [cited 2012 Aug 27]. Available from: http://clinicaltrials.gov/show/NCT00916552 NLM Identifier: NCT00916552.)
II. Biological Rationale
Over the past decade, as we have learned more about EPO’s diverse functions in the CNS, there has also been a fundamental re-conception of major depressive disorder, as a CNS process involving excess activation of pro-inflammatory cytokines and dysregulation of neural plasticity. Pro-inflammatory cytokines, including interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6) have been shown to be increased in individuals with MDD compared to healthy controls (Mossner et al., 2007; N. M. Simon et al., 2008; Zorrilla et al., 2001). In animal models, administration of pro-inflammatory cytokines or cytokine inducers have been associated with depression-like behavioral changes, including increased immobility time on the forced swim test, anhedonia, sleep disruption, and anorexia (Miller, Maletic, & Raison, 2009). These symptoms can be reversed through acute treatment with an anti-inflammatory cytokine (IL-10) or cytokine antagonist (IL-1RA), or chronic treatment with a serotonergic antidepressant (Dantzer, O'Connor, Freund, Johnson, & Kelley, 2008).
In humans, similar links between cytokine activity and mood changes have been established. Within the CNS, pro-inflammatory cytokines have been shown to modulate neurotransmitter systems, neurotrophic factors, and neurocircuitry associated with mood regulation. Approximately 20% to 50% of patients treated with the pro-inflammatory cytokine, interferon-alpha, for hepatits C or malignant melanoma will develop a clinical depression (Miller et al., 2009), and these rates can be dramatically reduced (approximately fourfold) following pre-treatment with the antidepressant, paroxetine (Musselman et al., 2001). In a study of patients with psoriasis, Tyring and colleagues found that individuals randomized to treatment with the TNF-alpha antagonist, etanercept, had significantly greater improvements in depressive symptoms (measured by the HAM-D-17) compared to controls; changes in core features of depression were only weakly correlated with objective measures of skin clearance and joint pain (Tyring et al., 2006). In a proof-of-concept study, Muller and colleagues found that depressed patients randomized to treatment with reboxetine combined with the COX-2 inhibitor, celecoxib, showed greater improvements in depression (measured by the HAM-D-17) compared to controls treated with reboxetine alone (Muller et al., 2006).
There is also now a substantial literature linking neurotrophic factors to the pathophysiology and treatment of major depressive disorder. In animal models, BDNF signaling in the hippocampus decreases under chronic stress conditions, and increases following ECT, or sustained treatment with several pharmacodynamically distinct antidepressants (SSRIs, NERIs, MAOIs) (Duman & Monteggia, 2006). Additionally, direct infusion of BDNF into the rodent hippocampus has been shown to induce neurogenesis and produce antidepressant-like effects (Santarelli et al., 2003; Shirayama, Chen, Nakagawa, Russell, & Duman, 2002) In a particularly exciting study, Tfilin and colleagues demonstrated that intracerebral infusion of mesechemyal stem cells also resulted in differentiation of new hippocampal neurons, and reduced behavioral measures of depression, such as immobility time on the the forced swim test (Tfilin et al., 2010). Currently, there are several neurotrophic agents in development for the treatment of depression. Inhibitors of phosphodiesterase 4 and 5 activate the cAMP system, and increase hippocampal BDNF expression (Fujimaki, Morinobu, & Duman, 2000). Rolpiram, a non-selective PDE-4 inhibitor, has been reported to reduce depressive symptoms in open (Zeller, Stief, Pflug, & Sastre-y-Hernandez, 1984) and controlled trials (Bertolino et al., 1988; Bobon et al., 1988; Fleischhacker et al., 1992).
ARA 290
Given EPO's anti-inflammatory and neurotrophic effects, both of which represent salient mechanisms of action for the treatment of MDD, and given empirical data that EPO has positive mood effects in healthy and depressed subjects, there is reason to believe it may represent a novel therapy for patients with treatment-resistant MDD. However, because EPO stimulates erythropoiesis, it also increases the risk of thromboembolic complications, hypertension and potentially malignant tumor growth (Jelkmann, Bohlius, Hallek, & Sytkowski, 2008; Miskowiak, Vinberg, Harmer, Ehrenreich, & Kessing, 2011). Therefore, a safer derivative of EPO, ARA 290, has recently been engineered.
ARA 290 is an 11-amino-acid EPO-derived peptide, which is non-erythropoietic, but retains therapeutic CNS properties. In animal models, ARA 290 has been shown to have CNS tissue protective properties (M. Brines & Cerami, 2008); decrease pro-inflammatory cytokines (McVicar et al., 2011); exert pro-cognitive effects (M. Brines et al., 2008); prevent programmed neuronal cell death (McVicar et al., 2011); and possibly promote neurogenesis (M. Brines et al., 2008). In humans, clinical trials are currently underway or in planning to evaluate its effect on neuropathy, rheumatoid arthritis, and cognition (http://araim.org/page-4/).
Summary and Significance
EPO is a highly promising, novel agent for the treatment of MDD. However, EPO’s side effect profile and burden of administration (e.g. high-dose IV infusions with weekly blood monitoring) will likely limit its clinical utility. In contrast, ARA 290 exhibits comparable efficacy for neural protection; target-engagement of EPO’s putative antidepressant mechanisms; and absence of serious side effects related to erythropoietic activity. No clinical trials have yet investigated ARA 290’s mood properties.
III. Potential collaborations
An academic institution could conduct any of the following studies to investigate additional mood-related indications for ARA 290 (including MDD, treatment-resistant MDD, post-stroke depression, and MDD co-morbid with chronic pain):
- A double-blind, randomized controlled trial of ARA 290 in healthy human subjects, employing innovative and evidence-based phase 1 technologies paired with emotional processing tasks to enhance signal detection of mood effects.
- A proof-of-concept study investigating the safety and efficacy of ARA 290 in the treatment of post-stroke depression. Note: this could be a particularly elegant extension of ARA 290’s neuroprotective benefits in post-stroke recovery.
- A proof-of-concept study investigating the safety and efficacy of ARA 290 in the treatment of patients with MDD co-morbid with chronic pain. Note: there is also emerging evidence that EPO reduces chronic pain, likely through its anti-inflammatory properties. Initial insults to peripheral and/or central nerves trigger the release of glutamate, activation of transcription factors (nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)), and increased synthesis of cytokines, chemokines and adhesion molecules. Pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6), can then cause pathological neural activation of glial cells that induce expression of cyclooxygenase (COX)-2, inducible nitric oxide (NO) synthase, and substance P. These inflammatory mediators act either directly on dorsal horn neurons that transmit pain (nociceptive neurons), or indirectly on primary afferents, with both processes leading to increased sensitivity of the nociceptive neurons (central sensitization) (DeLeo, 2006). In animal models of chronic or neuropathic pain, EPO has been shown to attenuate neuropathic pain behavior via inhibition of glial activation and activation of NF-κB, resulting in decreased production of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) and increased production of an anti-inflammatory cytokine interleukin-10 (IL-10) (H. Jia et al., 2009; H. B. Jia et al., 2009). EPO's antinociceptive effects may also be mediated by its ability to downregulate TNF-α mRNA expression by Schwann cells (Campana et al., 2006); and to increase JAK2 phosphorylation, a key anti-apoptotic signaling molecule for EPO-induced neuroprotection (Digicaylioglu & Lipton, 2001). Similar salutary effects on pain have been suggested for ARA 290 based on its anti-inflammatory properties and reduction of allodynia in preclinical models (Swartjes et al., 2011).
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