Pathological Disorders of the CNS
Acute and/or chronic injury to the CNS can result in the irreversible loss of function due to the inability of mature neurons to proliferate and compensate for the lost neurons. Furthermore, the nerves of the CNS cannot regenerate damaged axons. The neurons and glial cells that are still viable adjacent to the site of damage, cannot cope with the accumulating toxic intermediates that lead to additional progressive neuronal loss or secondary degeneration. Overcoming any of these obstacles could preserve or restore nerve function. Yet, the intricate and precise circuitry of the CNS requires a protective mechanism against inadvertent remodeling by immune cells during normal conditions. However, this restricted immune activity has resulted in few protective mechanisms and limited ability to regenerate axons as needed to reestablish contact between nerve cells following injury to the brain or spinal cord. Given these facts, Proneuron's strategy is to harness the immune system to reduce functional loss in pathological CNS disorders by inducing axonal regeneration and/or minimizing secondary degeneration.

Axonal Regeneration
Axonal regeneration (spinal nerve regeneration) is required for nerve function to be restored following either a spinal cord injury or optic nerve injury. Research comparing various species demonstrated that fish, which lack immune-privilege, are able to regenerate nerves of the CNS following injury; however, this ability diminishes as one moves up the evolutionary scale (Figure 1). The ability to regenerate nerves and the degree of immune privilege are therefore inversely related.

Correlation Between Regeneration and Immune Privilege in the CNS

Figure I. Inverse relationship between nerve regeneration and immune privilege.

Additional research in mammals has shown that while nerves in the immune privileged CNS are not capable of regeneration, the peripheral nervous system (PNS) is able to regenerate axons following injury, resulting in partial or complete functional recovery. Moreover, axons in the CNS can regrow into the stump of a peripheral nerve, revealing an intrinsic ability to regenerate when provided a permissive environment. The inflammatory response, and thus wound healing after injury differs between the mammalian PNS and CNS, in timing, quality, and extent. The goal of Proneuron's nerve-regeneration therapy is to overcome this innate deficit in CNS immune activity by implanting appropriately activated macrophages, to induce axonal regrowth.

Minimizing Neuronal Secondary Degeneration
Degeneration of neurons and glial cells result in accumulation of a myriad of toxic mediators leading to the eventual degeneration of viable neurons located in the proximity of the initial damage (secondary degeneration). These molecules serve key roles in normal neuronal function; however, when released into the tissue environment, they become toxic. In an attempt to minimize this damage, the traditional attempts are made to inhibit or neutralize these toxic intermediates. This strategy, while modestly effective in animal models, has failed to prove effective in human clinical trials. It is believed that since secondary degeneration is a complex and multifaceted process, it may not be feasible to target a single molecule. As previously mentioned, these mediators are required for normal neuronal function, therefore, while neutralizing these mediators at the site of injury may be effective it may have untoward effects on non-damaged tissue. Proneuron has taken an alternative approach, seeking to identify and leverage the body's own physiological mechanism of repair to create spinal nerve regeneration .

Research in the laboratory of Prof. Michal Schwartz has shown that utilization of the normal physiological response to CNS trauma as back injury, mediated by T-cells that accumulate at the injured site can be beneficial. Prof. Schwartz also demonstrated that secondary damage is more severe in T-cell deficient animals; however, augmenting the number of T-cells at the site of injury via boosting the T-cell immune response directed against a specific CNS antigen, improves neuronal survival after trauma. . A subsequent study demonstrated that rats with a partial crush injury of the optic nerve injected with myelin-protein-activated T-cells had a 2.5-fold increase in the survival of neurons, as compared to the control group (Nature Medicine, January 1999). Additional animal studies have demonstrated that this T-cell therapy is highly effective also in experimental partial spinal cord injury models (The Lancet, January 2000).