Toxicity and tolerability of recombinant human ciliary neurotrophic factor in patients with amyotrophic lateral sclerosis

Abstract

We examined the toxicity of both single and multiple subcutaneous injections of recombinant human ciliary neurotrophic factor (rhCNTF) in 72 patients with ALS, in doses ranging from 2 to 100 micrograms/kg. Adverse events were generally dose related and ranged from mild to severe. The tolerability of daily subcutaneous rhCNTF was equivalent to placebo at doses < or = 5 micrograms/kg/day. At higher doses, anorexia, weight loss, reactivation of herpes simplex virus (HSV1) labialis/stomatitis, cough, and increased oral secretions occurred.

Adenoviral cardiotrophin-1 gene transfer protects pmn mice from progressive motor neuronopathy

“…Indeed, we observed a reduction in weight gain and a dilatation of the left cardiac ventricle in AdCT-1-treated animals. Weight loss, proinflammatory responses, and induction of acute-phase proteins can be caused by several cytokines and have been extensively described after CNTF injection (21,(50)(51)(52). The stigmates of dilated cardiopathies that we observed in AdCT-1-treated normal mice are consistent with the morphological changes of cardiomyocytes cultured in the presence of CT-1 (53) and support the assumption that the neuroprotective effects of CT-1 in pmn mice might have been counterbalanced by its systemic toxicity.…”

Aging alters gene expression of growth and remodeling factors in human skeletal muscle both at rest and in response to acute resistance exercise

“…However, other studies suggest that CNTF can affect muscle excitation and reverse insulin resistance, and when used in muscle cultures CNTF regulates stem cell differentiation and protein synthesis, suggesting numerous mechanisms through which the ageassociated decrease in CNTF identified here could contribute to sarcopenia (11,45,63,65). Given these findings together with genetic studies showing that variations of CNTF and its receptor influence muscle strength and function (2,13,14,51) and that CNTF is being used in clinical trials for neurodegenerative disease (20,41), it is surprising that CNTF expression in human skeletal muscle has not been extensively quantified. Unfortunately, side-effects of weight loss and anorexia seen in the trial for treatment of neurodegeneration led to CNTF being tested in obesity.…”

Continued Administration of Ciliary Neurotrophic Factor Protects Mice from Inflammatory Pathology in Experimental Autoimmune Encephalomyelitis

“…50 So far, side effects of CNTF such as fever, malaise, and weight loss as well as the most likely poor ability of CNTF to cross the intact BBB have limited the success of clinical studies in amyotrophic lateral sclerosis patients who were given CNTF because of its known neuroprotective effect. 28,31,32 More promising results were obtained when CNTF was administered to the CNS by intrathecal injections or implantation of encapsulated transfected cells into the ventricular system. 34,36,37,81,82 Recent progress on human CNTF biochemistry indicated that this cytokine can use soluble or membrane-bound IL-6R␣ as a substitute to CNTFR␣ to activate the receptor signaling subunits, gp130 and LIFR␤.…”

“…28 -30 CNTF was administered systemically to patients with amyotrophic lateral sclerosis, but no beneficial effect was detected. 28,31,32 The lack of therapeutic efficiency could be linked to the poor ability of CNTF to pass the bloodbrain barrier (BBB). 33 More promising preclinical or clinical results have been obtained with CNTF targeted to the CNS by intrathecal injection or implantation of encapsulated transfected cells.…”