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

Abstract

BACKGROUND:

Brain derived neurotrophic factor (BDNF) is a potent survival factor for motoneurons. This study investigated the safety and tolerability of recombinant methionyl human BDNF (r-metHuBDNF) infused intrathecally by means of an implanted pump in patients with ALS.

METHODS:

Twenty-five patients with probable or definite ALS were treated with either r-metHuBDNF (25, 60, 150, 400 or 1000 microg/day) or placebo in a 12-week, randomized, double-blinded, sequential, dose-escalation study. Test treatment was interrupted by a washout period from days 11 to 25 to allow the evaluation of laboratory safety measures. In each dose cohort four patients received r-metHuBDNF and one received placebo. On completion of the double-blind period of the study all patients continued to receive r-metHuBDNF in an open-label extension for up to 60 weeks. Lumbar cerebrospinal fluid (CSF) samples were taken periodically from all patients for the measurement of r-metHuBDNF levels and in a minority of patients these were supplemented by cistemal samples.

RESULTS:

Within days after the initiation of infusion the majority of patients receiving r-metHuBDNF reported mild sensory symptoms, including paraesthesias or a sense of warmth, which were usually confined to the lower limbs and were frequently exacerbated by neck flexion. In most instances these symptoms decreased or even disappeared over several weeks. Sleep disturbance, dry mouth, agitation and other behavioural effects were encountered at higher doses (>150 microg/day) and necessitated dose reductions. The spinal CSF levels of r-metHuBDNF were directly related to dose, with a lumbar to cervical ratio of approximately 4:1.

CONCLUSIONS:

The intrathecal delivery of r-metHuBDNF in doses of up to 150 microg/day was well tolerated and appears feasible. The reversible CNS effects with higher dose indicate that BDNF can be delivered cranially against CSF flow. The small number of patients and the design of the study did not permit conclusions to be drawn about the efficacy of the treatment.

• Authors: G Ochs, R D Penn, M York, R Giess, M Beck, J Tonn, J Haigh, E Malta, M Traub, M Sendtner, K V Toyka
• Journal: Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases (Amyotroph Lateral Scler Other Motor Neuron Disord) Vol. 1 Issue 3 Pg. 201-6 (Jun 2000) ISSN: 1466-0822 [Print] England
• PMID: 11464953 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Brain-Derived Neurotrophic Factor
• Recombinant Proteins
• r-metHuBDNF protein, recombinant

Topics

• Adult
• Aged
• Amyotrophic Lateral Sclerosis (drug therapy)
• Brain-Derived Neurotrophic Factor (administration & dosage, adverse effects)
• Double-Blind Method
• Humans
• Injections, Spinal
• Middle Aged
• Paresthesia (chemically induced)
• Recombinant Proteins (administration & dosage, adverse effects)
• Sleep Wake Disorders (chemically induced)
• Smell (drug effects)
• Taste (drug effects)