Nanoparticle delivery of leukaemia inhibitory factor (LIF), of possible use in treating multiple sclerosis

Note text within published US patent application 20150231266:

Paragraph 2: The invention is in the field of compositions for neuroprotection, particularly compositions that promote and protect neural cells in the central nervous system of a mammal such as a human. Also described are methods for repairing tissues of the central nervous system of a mammal such as a human. Neurodegenerative diseases represent the largest area of unmet clinical need in the Western world. They are characterised by a progressive loss of the structure or function of neurons in the nervous system (neurodegeneration) and include Alzheimer's Disease (AD), Parkinson's Disease (PD) and a host of other rarer conditions such as Huntington's Disease (HD), Frontotemporal dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). The process of neurodegeneration is not well understood and so the diseases that stem from it have no effective cures, nor is it possible to slow down their progression, as yet.

Paragraph 90: In the CNS, LIF is thought to act predominantly as an injury factor, optimising the pool of neural precursors available for repopulation during repair (Pitman et al 2004, Mol Cell Neuroscience). LIF promotes neural stem cell self-renewal in the adult brain, regulating the emergence of more differentiated cell types, which ultimately leads to an expansion of the neural stem cell pool (Bauer, S. et al., 2006). LIF also stimulates the proliferation of parenchymal glial progenitors, in particular oligodendrocyte progenitor cells, through the activation of gp130 receptor signaling within these cells. This effect of LIF can be used to enhance the generation of oligodendrocytes and suggests that LIF has both reparative and protective activities that makes it a suitable candidate for the treatment of CNS demyelinating disorders and injuries (Deverman, B. E. et al., 2012). Furthermore, LIF has been shown to directly prevent oligodendrocyte death in animal models of multiple sclerosis, which is a disabling inflammatory demyelinating disease of the CNS, and this effect complements endogenous LIF receptor signalling, which already serves to limit oligodendrocyte loss during immune attack (Butzkueven, H. et al., 2002). LIF has also been shown to up-regulate the re-expression of NPCs in the brain of a Parkinson's Disease mouse model (Liu, J. et al., 2009).

Paragraph 102: The link between IL6, a potent inducer of pathogenic inflammatory TH17 lymphocytes and neurodegenerative disease progression is of further relevance, since the inventors have found that LIF directly suppresses both IL6 activity and TH17 cell development and instead promotes tolerogenic T.sub.reg cells (Gao et al 2009; Park et al 2011). This correlates with the recent finding that T.sub.reg opposes TH17-driven dopaminergic neurodegeneration in a mouse model of Parkinson's Disease (Reynolds et al 2010); and that LIF opposes pathogenic TH17 cells in an experimental allergic encephalitis (EAE) model of multiple sclerosis, a demyelinating disease of the CNS (Cao et al 2011).

Claim 18: The nanoparticle of claim 11, wherein the neurodegenerative disease is selected from the group consisting of: Alzheimer's Disease (AD), Multiple Sclerosis (MS); Parkinson's Disease (PD); Huntington's Disease (HD); Frontotemporal dementia (FTD); and Amyotrophic Lateral Sclerosis (ALS).


Also of relevance to multiple sclerosis, note published US application 20150366994, titled IMMUNO-MODULATORY COMPOSITION , first inventor Susan Metcalfe.

Paragraph 34:


The compositions of the invention are suitable for the treatment of autoimmune disorders. Local parenteral or subcutaneous delivery of the nanoparticle-comprising compositions of the invention into or around an inflamed joint can assist in amelioration of the symptoms of rheumatoid arthritis. Also, topical administration of an appropriate nanoparticle composition (i.e. as a lotion or skin cream) can be effective in treatment psoriasis. Finally, the nanoparticles can be incorporated into a time release depot formulation for longer term use, suitable for treatment of auto-immune encephalopathies and multiple sclerosis.


The first claim:


A composition for promoting an immune tolerance response in a mammal comprising: a) a pharmaceutically acceptable carrier solution; and b) a plurality of biodegradable polylactidecoglycolide (PLG) polymer nanoparticles, and wherein the PLG nanoparticles further comprise: (i) leukaemia inhibitory factor (LIF), wherein the LIF is encapsulated by the PLG nanaoparticle; and (ii) the PLG nanoparticles comprise an outer surface, wherein a targeting moiety that is able to bind selectively to an antigen present on the surface of a T lymphocyte cell is linked to the outer surface of the PLG nanoparticles.