Neurofibromatosis type 1 (NF1) is a common genetic syndrome that leads to tumor formation in the peripheral nervous system. Tumor growth within a peripheral nerve can lead to neurological symptoms including weakness, decreased sensation, and pain. The pain is often described as stabbing, shooting, or electrical pain, and can be elicited by touching the skin overlying the tumor. Surgical removal of the tumor often provides complete relief. However, a small percentage of patients may experience an increase in pain after surgery. This pain is due to the formation of a painful neuroma, a jumbled mass of nerve fibers and connective tissues, at the cut end of the nerve. The neuroma pain may resemble the preoperative pain. Unfortunately, the pain may cause significant disability and can persist despite multiple pharmacological and surgical treatments. The objective of this investigation is to further our understanding of the pathophysiology underlying the genesis of painful neuromas and to develop a definitive treatment.

Our laboratory has recently developed an animal (rat) model of a human painful neuroma. Stimulation of the skin overlying the neuroma produces a brisk paw withdrawal behavior. We believe that this behavioral response resembles the pain elicited by palpating the skin overlying a painful neurofibroma or painful neuroma in humans. Specific aim one is to refine this novel model so that it may be used as a tool to further our understanding of the mechanisms and treatment of painful neurofibromas and neuromas.

When a nerve sheath tumor is removed, at least some of the nerve fibers are cut. Neuroma formation is an inevitable consequence of cutting a peripheral nerve. Surgical removal of a painful neuroma may provide pain relief, but it is often short-lived because a new neuroma forms at the end of the nerve. A definitive method of preventing neuroma formation is to target and destroy those nerve fibers supplying the neuroma. In 1984 a novel approach for destroying neurons was introduced, which involves treating nerves with toxins that are taken up by distal nerve fibers and transported proximal to the cell bodies where they exert their lethal effects. This approach is known as "suicide transport." Saporin is a neural toxin that can be conjugated to OX7, an antibody to nerve. We have preliminary evidence that injecting OX7-saporin into a peripheral nerve can selectively target and destroy neurons and thus prevent neuroma formation. Specific aim two is to optimize our technique for treating peripheral nerves with OX7-saporin.

We hypothesize that treating a cut nerve with OX7-saporin will prevent the development of a neuroma. If a neuroma already exists, OX7-saporin may be used to remove the neuroma and prevent the formation of a new neuroma. Specific aim three will investigate whether OX7-saporin can prevent and/or reverse pain behavior in our animal model of painful neuroma. The results of these experiments will form the basis for future studies in primates and potentially humans. The refinement of our animal model will allow novel treatments to be tested. We believe that suicide transport may emerge as a definitive therapy to provide pain relief in patients with NF1.