SBIR-STTR Award

Our long-term objective is to develop drugs for the symptomatic treatment of peripheral neuropathies. Peripheral neuropathies are a diverse group of diseases (or syndromes) affecting a large population. Focal demyelination is known to occur in neuropathies, like Guillain-Barre Syndrome and Charcot-Marie-Tooth disease type l, resulting in delayed or blocked nerve conduction. Voltage-activated potassium channels normally do not play a significant role in mammalian axonal nerve conduction. However, demyelination leads to the exposure of paranodal potassium channels which dissipate the action potential by clamping the axon to the potassium equilibrium potential resulting in blocked nerve conduction. Blocking potassium channels exposed by demyelination provides an opportunity for symptomatic treatment. A high-throughput assay based on 96-well plate format has been established to screen an in-house library of 1700 compounds. using CHO cells stably expressing kv 1.1 channels. Our specific aims are to identify compounds that: 1) are potent in blocking Kv 1.1 channels, 2) exhibit a margin of safety in cardio-vascular tests, 3) can restore nerve conduction in an animal model of acute-demyelination by lysophosphatidyl choline, and 4) are poorly permeable through blood-brain- barrier. Such compounds will be considered for development as therapeutic agents. PROPOSED COMMERCIAL APPLICATION: Potassium channel blockers have commercial potential as important new pharmacological agents for clinical indications that are characterized by abnormal axonal conduction of nerve impulses. This project will lead to the development of small molecule therapeutics capable of improving motor and sensory function in patients suffering from peripheral neuropathies secondary to diabetes (an estimated 1 - 6.7 million cases as of 1991), chemotherapeutic treatment of Cancer (approximately 260,000 new cases/year). movement-related neuropathies and primary demyelinating diseases such as chronic inflammatory demyelinating polyradiculoneuropathy.

Thesaurus Terms:
drug screening /evaluation, inhibitor /antagonist, myelinopathy, neural conduction, polyneuritis, potassium channel acute idiopathic polyneuritis, bioassay, chemical registry /resource, chemical synthesis, guanidine, hereditary motor and sensory neuropathy, nervous system disorder chemotherapy, sciatic nerve, sign /symptom CHO cell, laboratory rat, rubidiumNational Institute of Neurological Disorders and Stroke (NINDS)

Our overall therapeutic goal is to develop a drug treatment that reduces suffering and improves quality of life for victims of peripheral neuropathies - a diverse group of neurological disorders with genetic, metabolic or toxic etiologies. Patients who suffer from peripheral neuropathy can experience loss of voluntary or involuntary motor function and a wide range of disordered sensations, including intense chronic pain. In peripheral neuropathies, demyelination of nerve axons is associated with loss of signal propagation that directly or indirectly causes the symptoms of the neuropathy. Exposure of specific voltage-gated potassium channels on nerve axons by demyelination creates a condition where the propagation of action potentials can be terminated by a "short circuit". Our mechanistic approach is to selectively block this specific class of voltage-gated potassium channels and restore axonal conduction in demyelinated peripheral nerves. In Phase I of the project, we successfully established the basic screening technologies, developed a focused chemical library of potassium channel blockers and identified lead molecules. In Phase II, we will study compounds from an expanded chemical library using in vitro assays and animal efficacy and safety "models" with the objective of selecting candidates for preclinical and clinical development. PROPOSED COMMERCIAL APPLICATION: Peripheral neuropathies afflict millions of people in the United States and tens of millions worldwide. For example, the NIDDK estimates that 16 million people in the US have diabetes and that 30-40% of diabetics have symptoms of peripheral neuropathy. In addition, certain drugs used in treating cancer cause an estimated 260,000 cases each year of peripheral neuropathy that can limit the use of the chemotherapeutic agents. There is no doubt that an effective drug treatment for the symptoms of peripheral neuropathy would have a substantial medical. societal and commercial impact.