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Vesicles comprising a pten inhibitor and uses of same

An inhibitor, vesicle technology, applied in the field of treatment of spinal cord injury, can solve problems such as cascade effect efficiency

Pending Publication Date: 2021-01-15
TECHNION RES & DEV FOUND LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The complexity of the cascade may affect the efficiency of proposed treatments and there remains an unmet need to develop other safe, effective and convenient approaches to treat SCI

Method used

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  • Vesicles comprising a pten inhibitor and uses of same
  • Vesicles comprising a pten inhibitor and uses of same
  • Vesicles comprising a pten inhibitor and uses of same

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0211] According to some embodiments, EVs can be loaded without the use of ultracentrifugation. According to another embodiment, said loading further comprises ultracentrifugation. According to some embodiments, the preparation method further comprises a step of purifying or isolating the loaded EVs. According to one embodiment, the separation is performed by centrifugation, for example ultracentrifugation. According to another embodiment, the separation is performed by filtration. According to one embodiment, the ratio of purified EVs to residual parental cells is at least 2, 3, 4, 5, 6, 8 or 10 times higher than it was in the starting material, or in certain advantageous embodiments at least 50, 100 or 1000 times. According to some embodiments, the EVs are cell-free EVs.

[0212] According to some embodiments, the present invention provides a method of preparing EVs such as exosomes, the method comprising incubating EVs with cholesterol-conjugated RNAi oligonucleotides (...

Embodiment 1

[0279] Example 1 - Intranasal MSC-Exo cross the blood-brain barrier and migrate to the spinal cord

[0280] The exosomes isolated from mesenchymal stem cell exosomes (MSC-Exo) had an average size of 111 ± 64 nm and a concentration of 40.43 x 108 particles / ml (Fig. S1D-E). MSC-Exo visualized with Cryo-TEM shows a typical spherical shape. To check whether MSC-Exo can cross the BBB, we labeled MSC-Exo with gold nanoparticles (GNP) as described in Betzer et al., 2017, ACS Nano 11, 10883-10893. Cryo-TEM imaging of GNP-loaded MSC-Exo showed that GNP was taken up by exosomes ( figure 1 ). To examine whether MSC-Exo could cross the blood-brain barrier after intranasal (IN) administration, GNP-loaded MSC-Exo were administered IN three hours after complete spinal cord transection. Micro-CT scans 24 hours after administration showed significant accumulation of GNP in lesioned areas of the spinal cord but not in the brain ( figure 2 , above). In contrast, in healthy controls, GNP wa...

Embodiment 2

[0283] Example 2. PTEN-siRNA loaded into MSC-Exo promotes robust DRG neuron outgrowth in vitro.

[0284] MSC-Exo were loaded with cholesterol-conjugated non-coding cy3-MAPK-siRNA as described in Materials and Methods. Nanosight analysis showed efficient cy3-MAPK-siRNA loading (33.64%) ( Figure 6 ).

[0285] To test whether PTEN inhibition delivered by siRNA-containing MSC-Exo could regulate axonal growth, self-delivered PTEN-siRNA was then loaded into MSC-Exo (hereinafter referred to as ExoPTEN) and added to dorsal root nerves in culture Ganglion (DRG) neurons. Compared with neurons treated with medium alone, non-targeting control siRNA (NTC-siRNA), MSC-Exo, or PTEN-siRNA alone, DRG neurons had more complex, branched, and elongated Morphology (Figure 7). At the median branching level, neurons treated with ExoPTEN exhibited a significantly higher number of branch points ( Figure 8 , one-way ANOVA, p<0.001, Tukey). ExoPTEN-treated neurons had significantly higher total n...

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Abstract

The present invention provides pharmaceutical compositions comprising membrane vesicles, including extracellular vesicles including those referred to as exosomes, loaded with an exogenous Phosphataseand tensin homolog (PTEN) inhibitor. Methods of treating neurological diseases, disorders or conditions using the extracellular vesicles are provided. Isolated extracellular vesicles loaded with an exogenous Phosphatase and tensin homolog (PTEN) inhibitor are provided as well.

Description

technical field [0001] The present invention relates to membranous vesicles loaded with PTEN inhibitors, pharmaceutical compositions comprising the vesicles, and their use in the treatment of neurological diseases, more particularly, to cell-derived vesicles loaded with exogenous PTEN inhibitors. Extracellular vesicles, pharmaceutical compositions comprising the vesicles, and their use for treating spinal cord injuries. Background technique [0002] Spinal cord injury may result in autonomic dysfunction, loss of sensation, or loss of mobility. This spinal cord injury (SCI) is caused by trauma, tumor, ischemia, developmental disturbance, neurodegenerative disease, demyelinating disease, transverse myelitis, vascular malformation or other causes. The consequences of SCI depend on the specific nature of the injury and its location in the spinal cord. Furthermore, since SCI is a dynamic process, in all acute spinal cord syndromes the extent of injury may not be apparent initia...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/127A61K31/7105A61K35/28A61P25/00C12N15/113
CPCA61K9/127A61K31/7088A61K35/28C12N15/1137C12N2310/14C12N2320/32C12N2310/3515C12Y301/03067A61K31/713A61K38/51C12Y402/02004A61K2300/00A61K9/1271A61P25/00A61K9/5068C12N15/111C12N15/113C12N2310/531
Inventor 舒拉米特·利文贝格郭绍伟丹尼尔·奥芬尼西姆·佩列茨
Owner TECHNION RES & DEV FOUND LTD
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