New York University

Bruce N Cronstein

Richard I Levin

Carmen Corciulo

Jan T Vilcek

Hans-Georg Wisniewski

Jonathan H Kaufman

Kathryn J Moore

Aranzazu Mediero Munoz

Abraham Ulman

Zhong Sheng Peng

Firas Mohamed Kara

Edwin Chan

Aranzazu Mediero-Munoz

Siddhesh R Angle

Linda Franks

Bhama Ramkhelawon

Zhongsheng Peng

Provided are liposomes that encapsulate adenosine. The liposomes may be formed from sphingomyelin or a combination of sphingomyelin and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) or a combination of sphingomyelin and 1,2-dimyristoyl-sn-glycero-3-phosphorylglycerol (DMPG) or a combination of sphingomyelin, DMPG, and DMPC. The liposomes encapsulating adenosine may be used to induce cartilage regeneration, treat osteoarthritis, alleviate joint pain, and/or slow, arrest, and/or reverse progressive structural tissue damage associated with osteoarthritis or treat osteoarthritis, rheumatoid arthritis, acute gouty arthritis, and/or synovitis. The liposomes may release adenosine for up to two weeks.

Liposomes encapsulating adenosine

The present invention relates to a polymeric nanoparticle conjugate of formula (I). The present invention also relates to pharmaceutical compositions including these polymeric nanoparticle conjugates, and methods of preparation and use thereof.

Biodegradable polymeric nanoparticle conjugates and use thereof

The invention provides methods and compositions for treating or inhibiting the development of osteoarthritis in a subject having osteoarthritis or at risk for developing osteoarthritis and for stimulating or increasing cartilage production or formation in a subject. The methods feature administering to the subject a therapeutically effective amount of a composition comprising one or more agent from among adenosine, an adenosine receptor agonist, and an agent that upregulates or increases the amount of or the biological activity of adenosine, or an analog or derivative thereof. The adenosine receptor may be an A, A, Aand Aadenosine receptor. The agent that upregulates or increases the amount of or the biological activity of adenosine may be dipyridamole or ticagrelor. The composition may be administered via intraarticular injection such as injection into the synovial fluid of a joint. The composition may be effective to reduce or inhibit degeneration or damage to cartilage or to stimulate or increase cartilage production or formation. The composition may be a liposomal composition or contain a liposome.

Methods and compositions for treating osteoarthritis and promoting cartilage formation

The invention provides methods and compositions for reducing or inhibiting osteolysis, bone resorption, osteoclast differentiation and stimulation and the loosening of medical prostheses by administering a compound or agent that inhibits the biological activity of an axon guidance protein. The compound or agent my inhibit transcription or translation of or bind to an axon guidance protein, such as, for instance, a netrin like netrin-1. Likewise, the compound or agent may inhibit transcription or translation of or bind to a receptor of an axon guidance protein, such as, for instance, a netrin receptor such as unc5b. In some instances, the compound or agent is an agonist of an adenosine Areceptor. The invention also extends to pharmaceutical compositions comprising such compounds and agents.

Methods for inhibiting osteolysis

The invention provides methods and compositions for reducing or inhibiting bone resorption, osteoclast differentiation and stimulation and the loosening of medical prostheses by administering a compound or agent that modulates an adenosine receptor such as the adenosine Areceptor, in particular, an agonist of an adenosine Areceptor. The invention also extends to pharmaceutical compositions comprising such an agent that modulates an adenosine receptor such as an adenosine Aagonist and to prosthetic devices containing such an agent that modulates an adenosine receptor such as an Aagonist on one or more surfaces or within the prosthetic device such as, for example, suspended in the cement forming the prosthetic device.

Medical implants containing adenosine receptor agonists and methods for inhibitiing medical implant loosening

Inhibition of bone resorption using medical implants containing adenosine receptor antagonists

The invention provides methods and compositions for modulating osteoclastogenesis and for treating bone diseases characterized by bone loss or a decrease in bone mass or density, by administering a compound or agent that modulates the adenosine A1 receptor, in particular, an inhibitor or antagonist of the A1 receptor.

Methods for inhibiting osteoclast differentiation, formation, or function and for increasing bone mass

Hepatic cirrhosis and fibrosis and fatty liver can be prevented and treated by administering to a subject in need thereof an effective amount of at least one adenosine A receptor antagonist or at least one adenosine uptake promotor.

Adenosine A2A receptor antagonists for treating and preventing hepatic fibrosis, cirrhosis and fatty liver

Pleiotropic pro-inflammatory cytokines, such as TNF and IL-1, induce expression of a protein molecule, termed TSG-6, in connective tissue cells. TSG-6, or pharmaceutical compositions containing TSG-6, can be used to treat inflammatory diseases and disorders and cancer-related pathologies. Inflammatory diseases and disorders, or cancer related pathologies, can also be treated by introducing human cells transfected with a DNA molecule containing a DNA segment encoding TSG-6 protein, into humans to express therapeutically effective amounts of TSG-6 in vivo or by introducing a vector carrying a DNA segment encoding TSG-6 protein directly into humans in vivo.

Pharmaceutical compositions containing TSG-6 for treating inflammatory diseases and cancer-related pathologies and method

Agonists of the adenosine A.sub.2 receptor promote the migration of endothelial cells, fibroblasts and epithelial cells. Thus, methods and pharmaceutical compositions useful for treating wounds and promoting wound healing comprise agents which cause stimulation of the adenosine A.sub.2 receptor, preferably receptor agonists and adenosine uptake blockers. Preferred agonists include 2-phenylaminoadenosine, 2-para-2-carboxyethylphenyl-amino-5'N-ethylcarboxamidoadenosine, 5'N-ethylcarbox-amidoadenosine, 5'N-cyclo-propyladenosine, 5'N-methylcarboxamidoadenosine and PD-125944. Preferred uptake blockers include dipyridamole, nitrobenzylthio-inosine, dilazep and R75231.

Adenosine receptor agonists for the promotion of wound healing

Agonists of the adenosine A.sub.2 receptor promote the migration of endothelial cells, fibroblasts and epithelial cells. Thus, methods and pharmaceutical compositions useful for treating wounds and promoting wound healing comprise agents which cause stimulation of the adenosine A.sub.2 receptor, preferably receptor agonists and adenosine uptake blockers. Preferred agonists include 2-phenylaminoadenosine, 2-para-2-carboxyethylphenyl-amino-5'N-ethylcarboxamidoadenosine, 5'N-ethylcarbox-amidoadenosine, 5'N-cyclopropyladenosine, 5'N-methyl-carboxamidoadenosine and PD-125944. Preferred uptake blockers include dipyridamole, nitrobenzylthio-inosine, dilazep and R75231.

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New York, NY, United States of America

Bruce N Cronstein