ddI and ddC are nucleoside analogues that have shown great promise in the treatment of AIDS and AIDS related complex. Unfortunately, phase I and II trials have revealed that both these agents cause a severe dose limiting sensory neuropathy which limits the potential usefulness of the two anti-viral agents. We propose to establish animal models of the toxic neuropathies and to extensively characterize them with the intent to further our understanding of their underlying mechanisms. We then plan to develop techniques of preventing the neuropathy in the clinical setting. Specifically, we plan to investigate which neuronal populations are affected, which components of the neurons, what neurotransmitter and enzyme abnormalities can be detected, and which structural components are involved, and over what time course. We also plan to test the ability of carefully selected neuronotrophic factors to prevent the toxic neuropathies in our model system as we have done successfully with other clinically important neurotoxins.
