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Neurotherapeutic Nanoparticle Compositions and Devices

a nanoparticle and nanotechnology, applied in the field of neuroprotection, can solve the problems of no effective cure, no effective cure, and no good cure for neurodegeneration, and achieve the effect of slowing down the progression of neurodegeneration

Inactive Publication Date: 2015-08-20
YALE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a composition for treating neurodegenerative diseases by targeting stem cells with biodegradable nanoparticles containing a targeting moiety and leukaemia inhibitory factor (LIF). The nanoparticles can be administered through various methods such as in vitro, ex vivo, or in vivo. The targeting moiety can bind to specific antigens on the surface of stem cells or other neural cells, allowing for specific delivery of the LIF. The nanoparticles can be designed to release the LIF over a period of time to effect timed release of the therapeutic agent. The stem cells can be selected from a variety of sources such as neural stem cells, totipotent stem cells, or induced pluripotent stem cells. The nanoparticles can be made of biodegradable polymers or liposomes. The use of these targeted nanoparticles can expand a population of stem cells with the capacity to act as neural precursor cells and potentially treat neurodegenerative diseases.

Problems solved by technology

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.
Chronic neurodegenerative disorders (NDD) of the central nervous system, which target the aging brain, are set to increase as the population ages and finding ways to better understand and treat these conditions is a major challenge given the personal and economic costs of these conditions.
However, as symptoms progress with time and coupled to the long-term use of dopaminergic drug therapies, a range of problems arise including the development of drug-induced motor complications such as “on-off” fluctuations and levodopa-induced dyskinesias (LID).
At this stage of the disease, drug therapies become increasingly disappointing in terms of a reliable therapeutic benefit.
These latter therapies can be effective, but only ever treat the symptoms without any attempt to repair the underlying and progressive disease.
Thus, these treatments also start to fail, in part because of this progressive nature of the non-nigral, non-motor aspects of Parkinson's Disease and in part because of the continued loss of nigral dopaminergic neurones.
Thus, NDD are characterised by a slow insidious progression with increasing misery for the patient and their family, and increasing burden on healthcare systems worldwide.
Early management is more in the community, but over time there are increasing co-morbidities that in turn greatly escalate costs in their management.
Thus, in cell therapy for PD, problems arise from the scarcity and ex vivo fragility of fetal dopaminergic cells.
However, such approachs have so-far failed to deliver substantial clinical benefits.
Whilst this exception proves that repair at the level of neuro-biochemistry is possible, viral-mediated delivery involves risk of unwanted side-effects due to viral components in addition to generating an immune response within the patient against the therapeutic protein itself.
Use of soluble growth factors alone is not simple, and may incur substantial off-target side-effects including the risk of carcinogenesis.

Method used

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  • Neurotherapeutic Nanoparticle Compositions and Devices
  • Neurotherapeutic Nanoparticle Compositions and Devices
  • Neurotherapeutic Nanoparticle Compositions and Devices

Examples

Experimental program
Comparison scheme
Effect test

example 1

1.1 Dopaminergic Neurons Derived from E14 Ventral Mesencephalon (VM) from Rat Foetuses Express the Components of the LIF Receptor Complex

[0117]The expression of gp130 and gp190, the two components of the LIF receptor complex (FIG. 1A), on dopaminergic neurons of embryonic day 14 ('E14′) VM was analysed via immunocytochemistry of E14 VM cultures after 3 days in vitro (DIV) (FIG. 1B). FIG. 1B shows that both components of the LIF receptor complex are expressed by dopaminergic neurons in E14 ventral mesencephalon (VM) cultures. FIG. 1A: The LIF receptor is a heterodimer consisting of two proteins: gp130 and gp190. FIG. 1B: Immunocytochemistry of 5 day old E14 VM cultures with antibodies against tyrosine hydroxylase and gp130 or gp190 demonstrated that dopaminergic neurons express gp130 and gp190. Dopaminergic neurons were demonstrated to express both gp130 and gp190, suggesting a potential for responsiveness to LIF treatment.

1.2 LIE Treatment during Tissue Dissociation Increases the Su...

example 2

2.1 Human: Monolayer and Neurosphere Cultures—Expansion of Cell Numbers to Provide Sufficient Cells for Testing Therapeutic LIE Nanoparticles

[0130]6-8 week old human foetal midbrain was dissected and cultured as neurospheres in proliferation medium before being sectioned and stained. Upon passage, parallel cultures as monolayer were grown in differentiation medium. Dopaminergic cells are positive for tyrosine hydroxylase (TH). Total cell numbers are stained with nuclear antigen (Hoechst). See FIG. 12, where: Primary=primary cultures; Passage 0=first subculture; Passage 1=second subculture.

[0131]Results show (i) maturation of TH+ neurons within the neurosphere microenvironment; (ii) differentiation of TH+ neurons grown in monolayer. Passage 2 also contains dopaminergic (DA) cells. These amplified cells were used to test LIF-nano effects on DA cell maturation and overall cell survival.

2.2 Human Foetal Ventral Mesencephalon LIF-Nanoparticle Therapy Enhances Human Dopaminergic Neuron De...

example 3

3.1 Treatment of Human Foetal Ventral Mesencephalon (hfVM) with LIF-Nanoparticle Therapy, or XAV939-Nanoparticle Therapy, Enhances Human Dopaminergic Neuron Derivation and Increases hfVM Cell Survival both In Vitro and In Vivo

[0133]To measure the effect of nanotherapy in vivo: hfVM cells were prepared as for the in vitro experiments as outlined in FIG. 17, primary human fetal mesencephalon tissue was stored at 4° C. for upto 4 days in Hibernate E storage medium. The cells were then seeded on coverslips and cultured 4d in differentiation medium after which cells were stained by DAPI to enumerate nuclei and for tyrosine hydroxylase to identify and enumerate differentiated dopaminergic cells. Pooled tissue was then prepared for cell transplantation following the clinical TransEuro Protocol. The protocol summarised in FIG. 18 follows that of the TransEuro clinical trial assessing hfVM cell grafts as cell therapy in patients with Parkinson's disease: http: / / www.transeuro.org.uk. The harv...

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Abstract

There are provided compositions and methods for treatment of neurodegeneative diseases and CNS injury. The compositions a pharmaceutically acceptable carrier solution; and a plurality of biodegradable nanoparticles, wherein the nanoparticles comprise a targeting moiety that is able to bind selectively to the surface of a neural stem cell and wherein the nanoparticles further comprise factors such as leukaemia inhibitory factor (LIF); XAV939 and / or one or more of : brain-derived neurotrophic factor (BDNF) or an agonist thereof; epidermal growth factor (EGF) or an agonist thereof; glial cell-derived neurotrophic factor (GDNF) or an agonist thereof; retinoic acid and derivatives thereof; ciliary neurotrophic factor (CTNF) or an agonist thereof; and Wnt5A. The biodegradable nanoparticles may deliver via controlled time release.

Description

RELATED APPLICATIONS[0001]This application is a continuation of International Application No. PCT / US2013 / 056246, which designated the United States and was filed on Aug. 22, 2013, published in English, which claims the benefit of U.S. Provisional Application No. 61 / 692,519, filed on Aug. 23, 2012 and U.S. Provisional Application No. 61 / 707,723, filed on Sep. 28, 2012. The entire teachings of the above applications are incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]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 (neur...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K47/42A61K9/48A61K38/20
CPCB82Y5/00A61K38/1808A61K38/185A61K38/2093C07K16/2863A61K47/6907A61K38/204A61P25/16A61P25/28A61K2300/00A61K9/4866A61K47/42
Inventor METCALFE, SUSAN MARIEFAHMY, TAREK
Owner YALE UNIV
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