Treatment of multiple sclerosis with long acting glatiramer and adipose-derived stem cells
Inventors
Marom, Ehud • BLEICH KIMELMAN, Nadav • Grynspan, Frida
Assignees
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Publication Number
US-11413311-B2
Publication Date
2022-08-16
Expiration Date
Abstract
Methods of treating multiple sclerosis are provided, comprising parenterally administering glatiramer acetate in a sustained-release depot form, and administering adipose-derived stem cells into the central nervous system. According to some aspects the combined treatments provide synergistic effects. In particular the combined therapies offer benefits to progressive forms of multiple sclerosis.
Core Innovation
The invention relates to a method of treating multiple sclerosis by administering a synergistic combination to a subject in need thereof. The combination comprises a pharmaceutical composition comprising glatiramer acetate in a sustained release depot form administered parenterally, and human adipose-derived stem cells (hADSCs) administered into the central nervous system (CNS). The CNS delivery is described for intrathecal and intraventricular administration.
The approach is directed to multiple sclerosis, with emphasis on progressive MS. The background problem addressed is the need for treatment of multiple sclerosis, including progressive forms, using a therapeutic strategy that provides superior or longer efficacy compared with administration of either long-acting glatiramer depot or adipose-derived stem cells alone. The invention rationale is supported by an extensive preclinical EAE experimental framework with clinical score-based outcomes and statistical comparisons.
In one aspect, the hADSCs are defined as isolated hADSCs that are sub-cultured to a passage number between 3 and 10 passages. The document further describes characterizing hADSCs by marker expression and describes routes and timing options for administering the sustained-release depot glatiramer acetate and the hADSCs relative to one another. The sustained-release glatiramer acetate depot is described as a depot/microparticle system using specified formulation characteristics, including microparticle/carrier systems.
Claims Coverage
The independent claim covers a treatment method for multiple sclerosis that requires a synergistic combination of (i) a sustained-release depot form of glatiramer acetate administered parenterally and (ii) hADSCs administered into the CNS, with additional defining constraints on the hADSC preparation in dependent claim refinements. Main inventive features include the synergistic combination and the CNS delivery, with further feature selection based on hADSC passage range and additional identity/characterization and depot formulation attributes stated in dependent claims.
Synergistic combination of sustained-release glatiramer acetate depot and hADSCs
A method of treating multiple sclerosis comprising administering to a subject in need thereof a synergistic combination of (i) a pharmaceutical composition comprising glatiramer acetate, the pharmaceutical composition being in a sustained release depot form administered parenterally, and (ii) human adipose-derived stem cells (hADSCs) administered into the central nervous system (CNS) of the subject.
hADSCs isolated and sub-cultured to a passage number between 3 and 10 passages
The method wherein the hADSCs are isolated hADSCs sub-cultured to a passage number between 3-10 passages.
hADSC passage number refinement
The method wherein the hADSCs are isolated hADSCs and sub-culturing them to a passage number between 4 and 5.
hADSC marker expression thresholds
The method includes characterizing hADSCs by positive and negative marker expression thresholds across percentages of cells.
Sustained-release depot carrier selection
The method is carried out using a carrier selected from the group consisting of PLGA, PLA, PGA, polycaprolactone, polyhydroxybutyrate, polyorthoesters, polyalkaneanhydrides, gelatin, collagen, oxidized cellulose, and polyphosphazene.
Microparticles prepared by water-in oil-in water double emulsification
The method includes formulating a pharmaceutical composition containing glatiramer acetate as microparticles prepared by a water-in oil-in water double emulsification process.
Glatiramer acetate acetate salt composition with specified molar ratios
The method includes that glatiramer acetate contains acetate salts of L-alanine, L-glutamic acid, L-lysine, and L-tyrosine in specified molar ratios.
Overall claim coverage centers on treating multiple sclerosis using a synergistic combination of a sustained-release glatiramer acetate depot administered parenterally and hADSCs administered into the CNS. Refinements include specifying the hADSC passage range and marker characterization, and defining sustained-release depot formulation aspects such as carrier selection and microparticle preparation, as well as the glatiramer acetate acetate-salt composition.
Stated Advantages
Superior/longer efficacy compared with administration of long-acting glatiramer depot alone or adipose-derived stem cells alone.
Potential GA dose reduction while maintaining or improving efficacy.
Documented Applications
Treatment of multiple sclerosis, including progressive MS (SPMS and PPMS), by administering a synergistic combination of parenteral sustained-release glatiramer acetate depot and CNS-delivered hADSCs.
Preclinical EAE evaluation using clinical score-based outcomes, disease onset measures, AUC, and statistical comparisons.
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