Nogo, caspr, f3 nb-3 useful in the treatment of injury and disease to the central nervous system

Abstract

The application provides materials and methods for promoting myelination of neuronal axons in the CNS. These derive from the findings firstly that the molecules Nogo and Caspr interact with one another during establishment and maintenance of the axoglial junction, and secondly that the molecules F3 and NB-3 are capable of promoting oligodendrocyte maturation via interaction with Notch. The materials and methods provided may be used in the treatment of CNS damage, in particular the treatment of spinal cord injury, multiple sclerosis, epilepsy and stroke.

Description

FIELD OF THE INVENTION [0001] The present invention relates to novel methods and materials for treating injury and disease of the central nervous system (CNS). Particularly, but not exclusively, the invention provides methods and materials for spinal cord regeneration and remyelination following spinal cord injury (SCI), stroke, or disease such as multiple sclerosis (MS) and epilepsy. BACKGROUND TO THE INVENTION [0002] Over 250,000 people in the United States, and several million wordwide, are permanently disabled due to a past spinal cord injury (chronic SCI), and about 12,000 people are newly injured (acute SCI) in the United States each year. Additionally, paralysis due to SCI is predominantly a condition of the young: 60% of spinal cord injuries occur before age 30, and the most frequent incidence is at age 19. Most injuries are caused by motor vehicle, sports or work-related accidents, or by violence. Estimated costs of care for SCI patients in the United States alone exceed $9...

AI Technical Summary

Benefits of technology

[0070] The designing of mimetics to a known pharmaceutically active compound is a known approach to the development of pharmaceuticals based on a “lead” compound. This might be desirable where the active compound is difficult or expensive to synthesise or where it is unsuitable for a particular method of administration, e.g. peptides are unsuitable active agents for oral compositions as they tend to be quickly degraded by proteases in the alimentary canal. Mimetic design, synthesis and testing is generally used to avoid randomly screening large number of molecules for a target property.

[0074] A template molecule is then selected onto which chemical groups which mimic the pharmacophore can be grafted. The template molecule and the chemical groups grafted on to it can conveniently be selected so that the mimetic is easy to synthesise, is likely to be pharmacologically acceptable, and does not degrade in viva, while retaining the biological activity of the lead compound. Alternatively, where the mimetic is peptide based, further stability can be achieved by cyclising the peptide, increasing its rigidity. The mimetic or mimetics found by this approach can then be screened to see whether they have the target property, or to what extent they exhibit it. Further optimisation or modification can then be carried out to arrive at one or more final mimetics for in vivo or clinical testing.

[0079] Where bispecific antibodies are to be used, these may be conventional bispecific antibodies, which can be manufactured in a variety of ways (Holliger, P. and Winter G. Current Opinion Biotechnol. 4, 446-449 (1993)), eg prepared chemically or from hybrid hybridomas, or may be any of the bispecific antibody fragments mentioned above. It may be preferable to use scFv dimers or diabodies rather than whole antibodies. Diabodies and scFv can be constructed without an Fc region, using only variable domains, potentially reducing the effects of anti-idiotypic reaction. Other forms of bispecific antibodies include the single chain “Janusins” described in Traunecker et al, Embo Journal, 10, 3655-3659, (1991).

Problems solved by technology

However, the molecular mechanisms controlling the timing of OPC differentiation to OLs and the subsequent OL maturation remain poorly defined.

However, the previous studies have not identified the extracellular ligand that activates Notch / DTX1 signaling.

However, little is known about how neuronal molecules participate in OL generation from neural stem cells (NSCs).

However, constitutively active Notch1 alone fails to promote OL generation, suggesting that NB-3-induced NICD is required in this event.

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