Remyelination, Neuroprotection and Regeneration

Normal function of brain and spinal cord is dependent on neurons and their surrounding myelin. Myelin is the insulating layer of membranes that surrounds most nerve fibers. When a nerve fiber known as an axon is demyelinated, nerve impulses “short circuit” much like a wire whose insulation has been stripped. Neuronal death and demyelination occur in traumatic and degenerative conditions of the central nervous system (CNS), resulting in significant and often permanent disability.

Acorda preclinical technologies seek to address these problems by protecting neurons from death in acute and chronic conditions, preserving and restoring myelin and promoting regeneration and plasticity . These properties make the Acorda preclinical compounds promising potential therapeutics for the treatment of conditions including multiple sclerosis, Parkinson’s disease, stroke, traumatic brain injury and spinal cord injury.

Acorda’s remyelination programs include both growth factor and antibody approaches to stimulate repair of the damaged myelin sheath. The growth factors (neuregulins) also may prevent neuronal death and promote recovery following injury. Finally, Acorda is developing an enzyme technology (chondroitinases) to promote regeneration and plasticity.

What is Demyelination?

In 2002, Acorda acquired an exclusive worldwide license from CeNeS Pharmaceuticals. to its neuregulins intellectual property and related technology – a class of naturally occurring protein growth factors that have multiple effects on the nervous system and potential therapeutic applications in neurologic conditions.

The most clinically advanced of these agents, Glial Growth Factor 2 (GGF2), is a member of the neuregulin family of growth factors related to epidermal growth factor. The neuregulins bind to erbB receptors, which translate the growth factor signal to the cell and cause changes in cell growth, protein production and gene expression. The molecule was shown in published studies to stimulate remyelination in preclinical models of MS and to have a range of other effects in neural protection and repair.

The neuroprotection and repair properties of neuregulins have led to promising results in a range of CNS and peripheral nervous system (PNS) models of disease and injury. Acorda and its collaborators have demonstrated that neuregulins protect cells of the substantia nigra and preserve motor function in preclinical models of Parkinson’s disease. Neuregulins also protect brain and enhance recovery following both transient and permanent ischemia models of stroke. In addition, neuregulins protect central and peripheral neurons from chemically-induced death and dysfunction, such as following exposure to common chemotherapeutics. Acorda, through research in our own laboratories and those of our collaborators, continue active research and development activities with neuregulin as a potential therapy in the treatment of Parkinson’s disease, stroke, traumatic brain injury and peripheral nerve injury.

Neuregulins also have been shown to protect cardiomyocytes from a wide range of perturbations both in vitro and in vivo. Neuregulins have shown the ability to restore cardiac function in preclinical models of heart failure caused by myocardial infarction, rapid pacing, viral and chemically induced cardiomyopathies.

Acorda’s lead neuregulin, GGF2, has been advanced into formal preclinical development. Working with a contract manufacturer, cGMP manufacturing has been established and scaled to the 3000 liter scale. Acorda has also initiated a formal safety and toxicology program. Provided satisfactory results in the safety program and the ability to demonstrate sufficient manufacturing controls, Acorda anticipates filing an IND for GGF2 in early 2010 for an indication of heart failure. Acorda plans to capitalize upon the manufacturing and safety data to facilitate development of GGF2 for the neurological indications described above.

Acorda’s remyelinating antibody program is based on an exclusive license to patents derived from more than 15 years of research performed at the Mayo Clinic. The program is designed to promote remyelination of affected areas of the brain and spinal cord following disease or injury and have shown promise in animal models of MS.

Studies have demonstrated the ability of this family of antibodies to stimulate repair of the myelin sheath in three different preclinical models of MS. In particular, these antibodies were found to react with molecules on the surface of the cells that make the myelin sheath and stimulate them in a number of ways, leading to increased remyelination activity. These germ-line IgM antibodies were first identified in mice and similar antibodies were subsequently identified in human blood samples. The Mayo team and Acorda have been able to produce a recombinant human antibody that may be suitable for clinical development.

Acorda and our research partners at Mayo have selected a lead antibody known as recombinant human IgM 22 (rHIgM22). Manufacturing process development and pilot safety and toxicology are underway. Acorda will transfer these processes to a contract manufacturer and establish cGMP production to complete preclinical development.