Tolerability of recombinant-methionyl human neurotrophin-3 (r-metHuNT3) in healthy subjects

Chaudhry, Vinay; Giuliani, Michael J.; Petty, Brent G.; Lee, D.; Seyedsadr, Mahmoud; Hilt, Dana; Cornblath, David R.

doi:10.1002/(sici)1097-4598(200002)23:2<189::aid-mus7>3.0.co;2-8

Cited by 28 publications

(18 citation statements)

References 9 publications

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“…Similarly, there is relatively little evidence to suggest that peripheral TrkC receptors expressed by myelinated nerve fibers play a significant role in the generation and maintenance of pain in the adult. Thus, while local injection of NT-3 has been reported to induce mild pain at the injection site [30], other reports suggest that NT-3 does not sensitize nociceptive primary afferent fibers [20] and appears to be anti-nociceptive in some pain models such as complete Freund's adjuvant-induced skin inflammation [31]. …”

Section: Discussionmentioning

confidence: 99%

Administration of a Tropomyosin Receptor Kinase Inhibitor Attenuates Sarcoma-Induced Nerve Sprouting, Neuroma Formation and Bone Cancer Pain

et al. 2010

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Pain often accompanies cancer and most current therapies for treating cancer pain have significant unwanted side effects. Targeting nerve growth factor (NGF) or its cognate receptor tropomyosin receptor kinase A (TrkA) has become an attractive target for attenuating chronic pain.In the present report, we use a mouse model of bone cancer pain and examine whether oral administration of a selective small molecule Trk inhibitor (ARRY-470, which blocks TrkA, TrkB and TrkC kinase activity at low nm concentrations) has a significant effect on cancer-induced pain behaviors, tumor-induced remodeling of sensory nerve fibers, tumor growth and tumor-induced bone remodeling. Early/sustained (initiated day 6 post cancer cell injection), but not late/acute (initiated day 18 post cancer cell injection) administration of ARRY-470 markedly attenuated bone cancer pain and significantly blocked the ectopic sprouting of sensory nerve fibers and the formation of neuroma-like structures in the tumor bearing bone, but did not have a significant effect on tumor growth or bone remodeling.These data suggest that, like therapies that target the cancer itself, the earlier that the blockade of TrkA occurs, the more effective the control of cancer pain and the tumor-induced remodeling of sensory nerve fibers. Developing targeted therapies that relieve cancer pain without the side effects of current analgesics has the potential to significantly improve the quality of life and functional status of cancer patients.

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Section: Discussionmentioning

confidence: 99%

Administration of a Tropomyosin Receptor Kinase Inhibitor Attenuates Sarcoma-Induced Nerve Sprouting, Neuroma Formation and Bone Cancer Pain

et al. 2010

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“…Additionally, diabetes may result in decreased serum IGF and increased IGF-I binding protein-I [176], thereby inhibiting the protein's downstream effects. Despite increasing evidence that growth factors are suppressed in patients with diabetes, there is no direct link between neurotrophic factors and the pathogenesis of DPN [169] and preliminary studies of NGF [177] and NT3 treatment [47,178,179] have met with limited success.…”

Section: Neurotrophic Factorsmentioning

confidence: 99%

Pathophysiology and Treatment of Diabetic Peripheral Neuropathy: The Case for Diabetic Neurovascular Function as an Essential Component

Kles

Vinik²

2006

CDR

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Worldwide, diabetes and its complications are major causes of morbidity, decreased quality of life, mortality and increasing health care costs. Patients with diabetes attempt to control blood pressure, lipids and blood glucose levels to decrease their risk of macrovascular and microvascular complications, such as diabetic peripheral neuropathy (DPN). Even with control of these risk factors for vascular disease, many patients still develop complications. Targeted therapies to the underlying mechanisms of diabetic neuropathy are essential to slow the progression of the disease. This review describes the signs, symptoms and diagnosis of DPN. Additionally, new therapies and the complex etiology that contributes to the development of diabetic neuropathy are described (oxidative stress, hyperglycemia, advanced glycated end products, autoimmunity, neurotrophic factors and protein kinase C beta).

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“…Firstly, it would be straightforward to give hospitalised stroke patients subcutaneous infusions of recombinant NT-3. Secondly, Phase II clinical trials show that subcutaneous doses of NT-3 up to 150 µg/kg/day are well tolerated and safe in healthy humans and in humans with other conditions 18,19,21,35,36 , which paves the way for NT-3 as a therapy for stroke. We used a similar dose in this study: in future experiments we will optimize the dose and duration of treatment because it is possible that a different dose of NT-3 would promote additional recovery after stroke, especially if combined with appropriate rehabilitation 37 .…”

Section: Discussionmentioning

confidence: 99%

“…We chose to deliver NT-3 by the subcutaneous route for translational relevance. First, high, repeated subcutaneous doses of recombinant NT-3 are safe and well-tolerated in Phase I and II clinical trials for other disorders [18][19][20][21] . This is a clinically-straightforward route after ischemic stroke in humans.…”

Section: Introductionmentioning

confidence: 99%

Subcutaneous Neurotrophin-3 infusion induces corticospinal neuroplasticity and improvements in dexterity and walking in elderly rats after large cortical stroke

Duricki

Kakanos

Haenzi

et al. 2018

Preprint

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There is an urgent need for a therapy which reverses disability after stroke when initiated in a time frame suitable for the majority of new victims. Neurotrophin-3 (NT3) is a growth factor made by muscle spindles and skin which is required for the survival, development and function of locomotor circuits involving afferents from muscle and skin that mediate proprioception and tactile sensation.We set out to determine whether subcutaneous supplementation of NT3 improves sensorimotor recovery after stroke in elderly rats. We show that one-month-long subcutaneous infusion of NT3 protein induces sensorimotor recovery after cortical stroke in elderly rats. Specifically, in a randomised, blinded pre-clinical trial, we show improved dexterity, walking and sensory function in rats following cortical ischemic stroke when treatment with NT3 is initiated 24 hours after stroke. Importantly, NT-3 was given in a clinically-feasible timeframe via this straightforward route. MRI and histology showed that recovery was not due to neuroprotection, as expected given the delayed treatment. Rather, anterograde tracing showed that corticospinal axons from the less-affected hemisphere sprouted in the spinal cord from cervical levels 2 to 8. Importantly, Phase I and II clinical trials by others show that repeated, subcutaneously administered high doses of recombinant NT-3 are safe and well tolerated in humans with other conditions. This paves the way for NT-3 as a therapy for stroke.

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Tolerability of recombinant-methionyl human neurotrophin-3 (r-metHuNT3) in healthy subjects

Cited by 28 publications

References 9 publications

Administration of a Tropomyosin Receptor Kinase Inhibitor Attenuates Sarcoma-Induced Nerve Sprouting, Neuroma Formation and Bone Cancer Pain

Administration of a Tropomyosin Receptor Kinase Inhibitor Attenuates Sarcoma-Induced Nerve Sprouting, Neuroma Formation and Bone Cancer Pain

Pathophysiology and Treatment of Diabetic Peripheral Neuropathy: The Case for Diabetic Neurovascular Function as an Essential Component

Subcutaneous Neurotrophin-3 infusion induces corticospinal neuroplasticity and improvements in dexterity and walking in elderly rats after large cortical stroke

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