Neurotrophic factors and neurodegenerative disease

Neurodegenerative diseases are generally characterized by the death of specific neuronal populations. Many such neurons are responsive, in vitro at least, to one or more neurotrophic factor. This infers a potential therapeutic role for these molecules in the treatment of such conditions (Table 7.11). Lack of current effective therapies for the treatment of any neurodegenerative disease renders this avenue of investigation even more attractive. Target diseases include amyotrophic lateral sclerosis and peripheral neuropathies, as well as various neurodegenerative diseases of the brain, including Alzheimer s and Parkinson s. 

Disappointing initial clinical trials serve, however, to underline the fact that data from in vitro investigations or animal studies do not necessarily equate to a physiologically significant response in humans. 

as already discussed, is a condition characterized by degeneration of the spinal and brainstem motor neurons, resulting in muscle wasting and eventually death. It affects approximately 70000 people worldwide. Several neurotrophic factors known to positively influence motor neurons in vitro and/or in vivo (Table 7.11) have or are being assessed in clinical trials as therapeutic agents for ALS. 

Pre-clinical trials (as well as phase I and II clinical trials) utilizing CNTF yielded promising results, but the neurotrophic factor then failed phase III clinical trials on the basis of insufficient efficacy. However, myotrophin (IGF-1, produced by Cephalon Inc.) has proved more successful. A 266 patient phase III clinical study found that IGF-1 administration to ALS sufferers resulted in reduced severity of symptoms, and slower disease progression, although this or no related product has yet been approved for medical use. The potential world market for an ALS therapeutic agent approaches 1 billion. 

Peripheral neuropathy (degeneration of peripheral sensory and/or motor neurons) represents another target for neurotrophic intervention. It often occurs as a complication of diabetes or in cancer patients receiving chemotherapy. In severe cases, amputation of limbs affected by neuronal loss is warranted. Pre-clinical studies have clearly shown that sensory and sympathetic neurons depleted in peripheral neuropathy respond to NGF. Indeed, NGF, along with IGF-1, can prevent the occurrence of drug-induced peripheral neuropathy in animals. Human clinical trials continue. 

---