NSI-189 phosphate, a novel neurogenic compound, selectively benefits moderately depressed patients: A post-hoc analysis of a phase 2 study of major depressive disorder.

BACKGROUND: NSI-189 phosphate (NSI-189) is a novel neurogenic molecule with pleiotropic properties, including antidepressant, procognitive, synaptoplastic, and neurotrophic activities demonstrated in preclinical studies. Its antidepressant activity is monoamine-independent. NSI-189 was previously tested in patients with recurrent major depressive disorder in an inpatient setting. METHODS: This study involved 220 patients randomized to an NSI-189 40-mg dose, NSI-189 80-mg dose, or placebo daily for 12 weeks. The study utilized the sequential parallel comparison design, in which the drug effect was tested in 2 separate stages of 6 weeks each. Herein, post-hoc analyses of the data are presented. RESULTS: NSI-189's antidepressant effect increased when the participants' initial baseline depression severity was dichotomized along a Montgomery-Åsberg Depression Rating Scale (MADRS) score of 30. The NSI-189 80-mg dose showed significant benefit over placebo when utilizing the MADRS-6 (P = .046) in the subgroup of patients who were moderately depressed (MADRS < 30) but was not significant in patients who were severely depressed (MADRS ≥30). More pronounced procognitive effects were also observed in the moderate subgroup relative to the severe subgroup or the whole study group, in which 11/36 (31%), 5/36 (14%), or 7/36 (19%) of CogScreen variables significantly improved, respectively. CONCLUSIONS: These results suggest that NSI-189 is effective as a safe adjunctive therapy, with most compelling antidepressant and procognitive benefits noted in patients with moderate depression.

Stable Intracerebral Transplantation of Neural Stem Cells for the Treatment of Paralysis Due to Ischemic Stroke.

NSI-566 is a stable, primary adherent neural stem cell line derived from a single human fetal spinal cord and expanded epigenetically with no genetic modification. This cell line is being tested in clinical trials in the U.S. for treatment of amyotrophic lateral sclerosis and spinal cord injury. In a single-site, phase I study, we evaluated the feasibility and safety of NSI-566 transplantation for the treatment of hemiparesis due to chronic motor stroke and determined the maximum tolerated dose for future trials. Three cohorts (n = 3 per cohort) were transplanted with one-time intracerebral injections of 1.2 × 107 , 2.4 × 107 , or 7.2 × 107 cells. Immunosuppression therapy with tacrolimus was maintained for 28 days. All subjects had sustained chronic motor strokes, verified by magnetic resonance imaging (MRI), initiated between 5 and 24 months prior to surgery with modified Rankin Scores [MRSs] of 2, 3, or 4 and Fugl-Meyer Motor Scores of 55 or less. At the 12-month visit, the mean Fugl-Meyer Motor Score (FMMS, total score of 100) for the nine participants showed 16 points of improvement (p = .0078), the mean MRS showed 0.8 points of improvement (p = .031), and the mean National Institutes of Health Stroke Scale showed 3.1 points of improvement (p = .020). For six participants who were followed up for 24 months, these mean changes remained stable. The treatment was well tolerated at all doses. Longitudinal MRI studies showed evidence indicating cavity-filling by new neural tissue formation in all nine patients. Although this was a small, one-arm study of feasibility, the results are encouraging to warrant further studies. Stem Cells Translational Medicine 2019;8:999-1007.

Remediation of Radiation-Induced Cognitive Dysfunction through Oral Administration of the Neuroprotective Compound NSI-189.

Clinical management of primary and secondary central nervous system (CNS) malignancies frequently includes radiotherapy to forestall tumor growth and recurrence after surgical resection. While cranial radiotherapy remains beneficial, adult and pediatric brain tumor survivors suffer from a wide range of debilitating and progressive cognitive deficits. Although this has been recognized as a significant problem for decades, there remains no clinical recourse for the unintended neurocognitive sequelae associated with these types of cancer treatments. In previous work, multiple mechanisms have been identified that contribute to radiation-induced cognitive dysfunction, including the inhibition of neurogenesis caused by the depletion of radiosensitive populations of stem and progenitor cells in the hippocampus. To explore the potential neuroprotective properties of a pro-neurogenic compound NSI-189, Long-Evans rats were subjected to a clinically relevant fractionated irradiation protocol followed by four weeks of NSI-189 administered daily by oral gavage. Animals were then subjected to five different behavioral tasks followed by an analysis of neurogenesis, hippocampal volume and neuroinflammation. Irradiated cohorts manifested significant behavioral decrements on all four spontaneous exploration tasks. Importantly, NSI-189 treatment resulted in significantly improved performance in four of these tasks: novel place recognition, novel object recognition, object in place and temporal order. In addition, there was a trend of improved performance in the contextual phase of the fear conditioning task. Importantly, enhanced cognition in the NSI-189-treated cohort was found to persist one month after the cessation of drug treatment. These neurocognitive benefits of NSI-189 coincided with a significant increase in neurogenesis and a significant decrease in the numbers of activated microglia compared to the irradiated cohort that was given vehicle alone. The foregoing changes were not accompanied by major changes in hippocampal volume. These data demonstrate that oral administration of a pro-neurogenic compound exhibiting anti-inflammatory indications could impart long-term neurocognitive benefits in the irradiated brain.

Amelioration of Penetrating Ballistic-Like Brain Injury Induced Cognitive Deficits after Neuronal Differentiation of Transplanted Human Neural Stem Cells.

Penetrating traumatic brain injury (PTBI) is one of the major cause of death and disability worldwide. Previous studies with penetrating ballistic-like brain injury (PBBI), a PTBI rat model revealed widespread perilesional neurodegeneration, similar to that seen in humans following gunshot wound to the head, which is unmitigated by any available therapies to date. Therefore, we evaluated human neural stem cell (hNSC) engraftment to putatively exploit the potential of cell therapy that has been seen in other central nervous system injury models. Toward this objective, green fluorescent protein (GFP) labeled hNSC (400,000 per animal) were transplanted in immunosuppressed Sprague-Dawley (SD), Fisher, and athymic (ATN) PBBI rats 1 week after injury. Tacrolimus (3 mg/kg 2 days prior to transplantation, then 1 mg/kg/day), methylprednisolone (10 mg/kg on the day of transplant, 1 mg/kg/week thereafter), and mycophenolate mofetil (30 mg/kg/day) for 7 days following transplantation were used to confer immunosuppression. Engraftment in SD and ATN was comparable at 8 weeks post-transplantation. Evaluation of hNSC differentiation and distribution revealed increased neuronal differentiation of transplanted cells with time. At 16 weeks post-transplantation, neither cell proliferation nor glial lineage markers were detected. Transplanted cell morphology was similar to that of neighboring host neurons, and there was relatively little migration of cells from the peritransplant site. By 16 weeks, GFP-positive processes extended both rostrocaudally and bilaterally into parenchyma, spreading along host white matter tracts, traversing the internal capsule, and extending ∼13 mm caudally from transplantation site reaching into the brainstem. In a Morris water maze test at 8 weeks post-transplantation, animals with transplants had shorter latency to platform than vehicle-treated animals. However, weak injury-induced cognitive deficits in the control group at the delayed time point confounded benefits of durable engraftment and neuronal differentiation. Therefore, these results justify further studies to progress towards clinical translation of hNSC therapy for PTBI.

Transplantation of human fetal-derived neural stem cells improves cognitive function following cranial irradiation.

Treatment of central nervous system (CNS) malignancies typically involves radiotherapy to forestall tumor growth and recurrence following surgical resection. Despite the many benefits of cranial radiotherapy, survivors often suffer from a wide range of debilitating and progressive cognitive deficits. Thus, while patients afflicted with primary and secondary malignancies of the CNS now experience longer local regional control and progression-free survival, there remains no clinical recourse for the unintended neurocognitive sequelae associated with their cancer treatments. Multiple mechanisms contribute to disrupted cognition following irradiation, including the depletion of radiosensitive populations of stem and progenitor cells in the hippocampus. We have explored the potential of using intrahippocampal transplantation of human stem cells to ameliorate radiation-induced cognitive dysfunction. Past studies demonstrated the capability of cranially transplanted human embryonic (hESCs) and neural (hNSCs) stem cells to functionally restore cognition in rats 1 and 4 months after cranial irradiation. The present study employed an FDA-approved fetal-derived hNSC line capable of large scale-up under good manufacturing practice (GMP). Animals receiving cranial transplantation of these cells 1 month following irradiation showed improved hippocampal spatial memory and contextual fear conditioning performance compared to irradiated, sham surgery controls. Significant newly born (doublecortin positive) neurons and a smaller fraction of glial subtypes were observed within and nearby the transplantation core. Engrafted cells migrated and differentiated into neuronal and glial subtypes throughout the CA1 and CA3 subfields of the host hippocampus. These studies expand our prior findings to demonstrate that transplantation of fetal-derived hNSCs improves cognitive deficits in irradiated animals, as assessed by two separate cognitive tasks.