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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects both upper and lower motor neurons (MN) resulting in weakness, paralysis and subsequent death. Insulin-like growth factor-I (IGF-I) is a potent neurotrophic factor that has neuroprotective properties in the central and peripheral nervous systems. Due to the efficacy of IGF-I in the treatment of other diseases and its ability to promote neuronal survival, IGF-I is being extensively studied in ALS therapeutic trials. This review covers in vitro and in vivo studies examining the efficacy of IGF-I in ALS model systems and also addresses the mechanisms by which IGF-I asserts its effects in these models, the status of the IGF-I system in ALS patients, results of clinical trials, and the need for the development of better delivery mechanisms to maximize IGF-I efficacy. The knowledge obtained from these studies suggests that IGF-I has the potential to be a safe and efficacious therapy for ALS. [ABSTRACT FROM AUTHOR]

Significant progress in understanding the cellular mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis (ALS) has not been matched with the development of therapeutic strategies to prevent disease progression. The multiple potential causes and relative rarity of the disease are two significant factors that make drug development and assessment in clinical trials extremely difficult. We review recent progress in promoting therapeutics into clinical trials and highlight the value of moderate throughput screening for the acceleration and improvement of drug design. [Copyright &y& Elsevier]

Abstract: Objective: Intraspinal human spinal cord‐derived neural stem cell (HSSC) transplantation is a potential therapy for amyotrophic lateral sclerosis (ALS); however, previous trials lack controls. This post hoc analysis compared ambulatory limb‐onset ALS participants in Phase 1 and 2 (Ph1/2) open‐label intraspinal HSSC transplantation studies up to 3 years after transplant to matched participants in Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT) and ceftriaxone datasets to provide required analyses to inform future clinical trial designs. Methods: Survival, ALSFRS‐R, and a composite statistic (ALS/SURV) combining survival and ALS Functional Rating Scale revised (ALSFRS‐R) functional status were assessed for matched participant subsets: PRO‐ACT n = 1108, Ph1/2 n = 21 and ceftriaxone n = 177, Ph1/2 n = 20. Results: Survival did not differ significantly between cohorts: Ph1/2 median survival 4.7 years, 95% CI (1.2, ∞) versus PRO‐ACT 2.3 years (1.9, 2.5), P = 1.0; Ph1/2 3.0 years (1.2, 5.6) versus ceftriaxone 2.3 years (1.8, 2.8), P = 0.88. Mean ALSFRS‐R at 24 months significantly differed between Ph1/2 and both comparison cohorts (Ph1/2 30.1 ± 8.6 vs. PRO‐ACT 24.0 ± 10.2, P = 0.048; Ph1/2 30.7 ± 8.8 vs. ceftriaxone 19.2 ± 9.5, P = 0.0023). Using ALS/SURV, median PRO‐ACT and ceftriaxone participants died by 24 months, whereas median Ph1/2 participant ALSFRS‐Rs were 23 (P = 0.0038) and 19 (P = 0.14) in PRO‐ACT and ceftriaxone comparisons at 24 months, respectively, supporting improved functional outcomes in the Ph1/2 study. Interpretation: Comparison of Ph1/2 studies to historical datasets revealed significantly improved survival and function using ALS/SURV versus PRO‐ACT controls. While results are encouraging, comparison against historical populations demonstrate limitations in noncontrolled studies. These findings support continued evaluation of HSSC transplantation in ALS, support the benefit of control populations, and enable necessary power calculations to design a randomized, sham surgery‐controlled efficacy study. [ABSTRACT FROM AUTHOR]

Effective treatments are urgently needed for amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease characterized by the loss of motor neurons. In 2009, the FDA approved the first phase I safety trial of direct intraspinal transplantation of neural stem cells into patients with ALS, which is currently in progress. Stem cell technologies represent a promising approach for treating ALS, but several issues must be addressed when translating promising experimental ALS therapies to patients. This article highlights the key research that supports the use of stem cells as a therapy for ALS, and discusses the rationale behind and approach to the phase I trial. Completion of the trial could pave the way for continued advances in stem cell therapy for ALS and other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]