Effect of recombinant human insulin-like growth factor-I on progression of ALS

Abstract

The objective of this study was to investigate the safety and efficacy of recombinant human insulinlike growth factor-I (rhIGF-I) in the treatment of sporadic ALS. A double-blind, placebo-controlled, randomized study of 266 patients was conducted at eight centers in North America. Placebo or rhIGF-I (0.05 mg/kg/day or 0.10 mg/kg/day) was administered for 9 months. The primary outcome measure was disease symptom progression, assessed by the rate of change (per patient slope) in the Appel ALS rating scale total score. The Sickness Impact Profile (SIP), a patient-perceived, health-related quality of life assessment, was a secondary outcome variable. Progression of functional impairment in patients receiving high-dose (0.10 mg/kg/day) rhIGF-I was 26% slower than in patients receiving placebo (p = 0.01). The high-dose treatment group was less likely to terminate the study due to protocol-defined markers of disease symptom progression, and members in this group exhibited a slower decline in quality of life, as assessed by the SIP. Patients receiving 0.05 mg/kg/day of rhIGF-I exhibited trends similar to those associated with high-dose treatment, suggesting a dose-dependent response. The incidence of clinically significant adverse experiences was comparable among the three treatment groups. Recombinant human insulin-like growth factor-I slowed the progression of functional impairment and the decline in health-related quality of life in patients with ALS with no medically important adverse effects.

Up-Regulation of Insulin-Like Growth Factor-II Receptor in Reactive Astrocytes in the Spinal Cord of Amyotrophic Lateral Sclerosis Transgenic Rats

“…Several studies have reported positive effects of IGF-I in reducing motor neuron death, delaying the onset of motor performance decline and the increasing life span in SOD1 mouse models of ALS and in one clinical trial. The IGF-1 studies in humans have reported that the progression of functional impairment in patients receiving high doses of IGF-1 was reduced by 26% vs patients receiving placebo (Lai et al 1997). However, a second clinical trial produced no positive results (Borasio et al 1998), and there currently is a phase III randomized, double-blind, placebo-controlled clinical IGF-1 trial underway.…”

Antiapoptotic activity maintenance of Brain Derived Neurotrophic Factor and the C fragment of the tetanus toxin genetic fusion protein

“…In vitro studies demonstrated that several neurotrophic factors delay motorneuron degeneration [3][4][5][6]. However, clinical trials using subcutaneous and intrathecal neurotrophic factors caused several side effects such as weight loss, fever, cough, fatigue and behavioural changes [7][8][9][10][11][12].…”

αCAR IGF‐1 vector targeting of motor neurons ameliorates disease progression in ALS mice

“…IGF‐1 is known to have a neurotrophic effect on motor neurons 30. To date IGF‐1 ‐based therapies have little beneficial effect upon systemic or intrathecal administration in ALS patients 19, 20, 21. The poor outcomes of these studies may possibly be due to low availability of IGF‐1 as free IGF‐1 is reduced while IGF‐1 R expression is upregulated in both the CNS and muscle of ALS patients 31, 32.…”

“…In recent years, many studies have focused on gene delivery of growth factors to the central nervous system (CNS) in order to slow disease progression in animal models of ALS utilizing the intramuscular,10, 11, 12, 13 intracerebral,14, 15 intracerebroventricular16, and intraspinal17, 18 routes of administration. Despite the encouraging results of these studies, subcutaneous delivery of recombinant human insulin‐like growth factor 1 IGF‐1 ( rhIGF‐1) in ALS patients had little effect in 3 clinical trials 19, 20, 21. Each of these approaches has its own limitations which may negate achieving efficacy in ALS patients.…”