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Basic Fibroblast Growth Factor Does Not Prolong Survival in a Transgenic Model of Familial Amyotrophic Lateral Sclerosis

M. N. Upton-Rice, BS,* M. E. Cudkowicz, MD, MSc,*†‡ L. Warren, BA,* R. K. Mathew, BA,* J. M. Ren, MD,†S. P. Finklestein, MD,† and R. H. Brown, Jr, MD, DPhil*†

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting motor neurons in the spinal cord and brain. Ten percent of all ALS cases are familial; 25% of these cases have a mutation in the gene that encodes cytosolic Cu/Zn superoxide dismutase. Mice that express mutant superoxide dismutase 1 molecules die from a motor neuron degeneration resembling human ALS.1

Neuroprotective agents such as basic fibroblast growth factor (bFGF) may prolong survival in ALS mice. bFGF is a growth factor that crosses the blood-brain barrier when administered by subcutaneous injection and has trophic effects on neurons and glial cells.2 bFGF also protects neurons against excitotoxicity and oxidative stress.2 We therefore analyzed the effect of bFGF on disease phenotype in ALS mice.

Beginning at 30 days of age, mice received bFGF by intraperitoneal injection twice weekly at doses of 0, 15, 100, 200, or 500 mg/kg. Onset of disease was defined by the appearance of tremulousness and weakness in the hind limbs. Euthanasia was performed when animals were too weak to roll over in 30 seconds.

bFGF had no effect on onset of clinical disease or survival in the ALS mice. Mean lengths of survival for the trial groups were: 133.45 days (SD, 9.3; 0 mg/kg; n 5 20), 129.33 days (SD, 12.8; 15 mg/kg; n 5 24), 126.29 days (SD, 15.8; 100 mg/kg; n 5 21), 130.75 days (SD, 11.5; 200 mg/kg; n 5 8), and 132.29 days (SD, 10.4; 500 mg/kg; n 5 7).

Survival has been prolonged in these ALS transgenic mice by riluzole, gabapentin,3 creatinine,4 and D-penicillamine.5 N-Acetylcysteine and two neuronal nitric oxide inhibitors had no effect on survival in this mouse model. Our current results suggest that intraperitoneal injections of bFGF also do not delay motor neuron death in this mouse model of familial ALS.

*Day Neuromuscular Research Laboratory, †Department of Neurology, and ‡Clinical Trial Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA

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Biotrofix is a premier preclinical contract research organization specializing in animal models of CNS, cardiac and vascular disease. With years of experience, both academic, commercial, clients throughout the biotech and pharmaceutical industries, Biotrofix delivers industry-leading preclinical CRO services, including rodent models of acute stroke and stroke recovery, preclinical CRO services for Alzheimer's Disease, transgenic animal models for ALS, as well as CRO services for brain injury, preclinical CRO services for spinal cord injury and related cardiac drug discovery and development.