A phase I/II trial of recombinant methionyl human brain derived neurotrophic factor administered by intrathecal infusion to patients with amyotrophic lateral sclerosis

Ochs, G.; Penn, Richard D.; York, Michelle M.; Giess, Ralf; Beck, Marcus; Tonn, Jörg C.; Haigh, J. R. M.; Malta, Errol; Traub, Michael; Sendtner, Michael; Toyka, Klaus V.

doi:10.1080/14660820050515197

Cited by 267 publications

(143 citation statements)

References 12 publications

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“…Thirteen of 20 amyotrophic lateral sclerosis (ALS) patients receiving intrathecal BDNF reported sensory symptoms, and 9 reported behavioral effects. 23 Animal studies have additionally shown induction of muscle spasticity at 4 weeks after AAV-mediated delivery of BDNF. 28,29 The potential adverse effects of BDNF were not an outcome of the current study design; therefore, allodynia or spasticity was not systematically assessed.…”

Section: Role Of Bdnf On Functional Recovery After Spinal Cord Injurymentioning

confidence: 99%

“…Importantly, recovery of ipsilateral diaphragm activity after SH can be enhanced by intrathecal delivery of BDNF at the level of the phrenic motor nucleus. 14 Unfortunately, nonlocalized administration of BDNF by systemic, 22 or even intrathecal, treatment 23,24 in human studies is linked to adverse effects, mainly related to altered sensory processing and pain, [25][26][27] muscle spasticity, 28,29 and other behavioral effects 22 that prevent its therapeutic use.…”

Section: Introductionmentioning

confidence: 99%

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Localized Delivery of Brain-Derived Neurotrophic Factor-Expressing Mesenchymal Stem Cells Enhances Functional Recovery following Cervical Spinal Cord Injury

Gransee

Zhan

Sieck

et al. 2015

Journal of Neurotrauma

116

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Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are important in modulating neuroplasticity and promoting recovery after spinal cord injury. Intrathecal delivery of BDNF enhances functional recovery following unilateral spinal cord hemisection (SH) at C2, a well-established model of incomplete cervical spinal cord injury. We hypothesized that localized delivery of BDNF-expressing mesenchymal stem cells (BDNF-MSCs) would promote functional recovery of rhythmic diaphragm activity after SH. In adult rats, bilateral diaphragm electromyographic (EMG) activity was chronically monitored to determine evidence of complete SH at 3 days post-injury, and recovery of rhythmic ipsilateral diaphragm EMG activity over time post-SH. Wild-type, bone marrow-derived MSCs (WT-MSCs) or BDNF-MSCs (2 · 10 5 cells) were injected intraspinally at C2 at the time of injury. At 14 days post-SH, green fluorescent protein (GFP) immunoreactivity confirmed MSCs presence in the cervical spinal cord. Functional recovery in SH animals injected with WT-MSCs was not different from untreated SH controls (n = 10; overall, 20% at 7 days and 30% at 14 days). In contrast, functional recovery was observed in 29% and 100% of SH animals injected with BDNF-MSCs at 7 days and 14 days post-SH, respectively (n = 7). In BDNF-MSCs treated SH animals at 14 days, root-mean-squared EMG amplitude was 63 -16% of the pre-SH value compared with 12 -9% in the control/WT-MSCs group. We conclude that localized delivery of BDNF-expressing MSCs enhances functional recovery of diaphragm muscle activity following cervical spinal cord injury. MSCs can be used to facilitate localized delivery of trophic factors such as BDNF in order to promote neuroplasticity following spinal cord injury.

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Section: Role Of Bdnf On Functional Recovery After Spinal Cord Injurymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Localized Delivery of Brain-Derived Neurotrophic Factor-Expressing Mesenchymal Stem Cells Enhances Functional Recovery following Cervical Spinal Cord Injury

Gransee

Zhan

Sieck

et al. 2015

Journal of Neurotrauma

116

View full text Add to dashboard Cite

show abstract

“…Human phase I/II trials of recombinant methionyl human BDNF have already been undertaken, wherein the BDNF was administered by intrathecal infusion to patients with amyotrophic lateral sclerosis (Ochs et al 2000). Unfortunately, side effects such as sensory symptoms, including paraesthesias or a sense of warmth, sleep disturbance, dry mouth, agitation, and other behavioral effects were encountered at higher doses, precluding further study.…”

Section: Strategies To Potentiate the Creb/bdnf/ Bcl-2 Cascade For Thmentioning

confidence: 99%

Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for Difficult-to-Treat depression

Manji

Quiróz

Sporn

et al. 2003

Biological Psychiatry

445

259

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“…BDNF is of particular therapeutic interest because of its neurotrophic actions on neuronal populations involved in several disorders, including amyotrophic lateral sclerosis (4), Parkinson disease, and Alzheimer's disease (5). However, clinical trials using recombinant BDNF have been disappointingly negative (6), presumably because of poor delivery, short half-life, and other limitations. Although efforts have been made to circumvent these problems (7,8), no exogenous agents have been identified that act as potent and selective in vivo agonists of TrkB.…”

mentioning

confidence: 99%

A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone

Jang

Liu²,

Yepes³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

609

595

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Brain-derived neurotrophic factor (BDNF), a cognate ligand for the tyrosine kinase receptor B (TrkB) receptor, mediates neuronal survival, differentiation, synaptic plasticity, and neurogenesis. However, BDNF has a poor pharmacokinetic profile that limits its therapeutic potential. Here we report the identification of 7,8-dihydroxyflavone as a bioactive high-affinity TrkB agonist that provokes receptor dimerization and autophosphorylation and activation of downstream signaling. 7,8-Dihydroxyflavone protected wild-type, but not TrkB-deficient, neurons from apoptosis. Administration of 7,8-dihydroxyflavone to mice activated TrkB in the brain, inhibited kainic acid-induced toxicity, decreased infarct volumes in stroke in a TrkB-dependent manner, and was neuroprotective in an animal model of Parkinson disease. Thus, 7,8-dihydroxyflavone imitates BDNF and acts as a robust TrkB agonist, providing a powerful therapeutic tool for the treatment of various neurological diseases.

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A phase I/II trial of recombinant methionyl human brain derived neurotrophic factor administered by intrathecal infusion to patients with amyotrophic lateral sclerosis

Cited by 267 publications

References 12 publications

Localized Delivery of Brain-Derived Neurotrophic Factor-Expressing Mesenchymal Stem Cells Enhances Functional Recovery following Cervical Spinal Cord Injury

Localized Delivery of Brain-Derived Neurotrophic Factor-Expressing Mesenchymal Stem Cells Enhances Functional Recovery following Cervical Spinal Cord Injury

Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for Difficult-to-Treat depression

A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone

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