Neurotrophic factors and neuromuscular disease: I. General comments, the neurotrophin family, and neuropoietic cytokines - II. GDNF, other neurotrophic factors, and future directions

Neurotrophic factors are growth factors or cytokines that are inducible pol ypeptides and permit intercellular communication. An explosion of informati on about neurotrophic factors is setting the stage for significant advances in neural disease therapy in the next century. The effects of these trophi c factors are overlapping and pleiotropic, acting on many cell types and ti ssues to control proliferation and differentiation of developing neurons an d to exert a variety of functions on mature neurons. Studies of receptors u nique to several neurotrophic factor families have revealed exquisite mecha nisms of signal transduction. Preclinical trials in neuromuscular disease w ere promising, but results from initial clinical trials have been disappoin ting; new and better designed clinical trials are under way. Laboratory inv estigators also are exploring techniques to deliver factors directly to the central nervous system by means of viral vectors or to exert neurotrophic signals on the nervous system using novel small molecules that stimulate ne urotrophic factor or neuroimmunophilin receptors. Combination therapies, re fined delivery techniques, and treatment timing may be the key for successf ul treatment with neurotrophic factors. In this two-part review, we discuss the neurobiology of neurotrophic factors, the characteristics of the major neurotrophic factors, and their therapeutic potential in neuromuscular dis ease. This is the second of two reviews in which we discuss the essential aspects of neurotrophic factor neurobiology, the characteristics of each neurotrop hic factor, and their clinical relevance to neuromuscular diseases. The pre vious paper reviewed the neurotrophin family and neuropoietic cytokines. In the present article, we focus on the GDNF family and other neurotrophic fa ctors and then consider future approaches that may be utilized in neurotrop hic factor treatment. (C) 1999 John Wiley & Sons, Inc.