Methods of increasing delivery of active agents to brain comprising administering receptor associated protein (RAP) fragments conjugated to active agents
View Patent ↗The present invention is directed to a methods and compositions for receptor mediated drug delivery, particularly across the blood-brain barrier.
1. A method of delivering an active agent into the central nervous system of an animal comprising administering to said animal a conjugate comprising said agent conjugated to a Receptor Associated Protein (RAP) polypeptide consisting of an amino acid sequence at least 80% identical to amino acids 221-323 of RAP (SEQ ID NO: 1), wherein said agent is delivered into the central nervous system.
2. A method of increasing transcytosis of an active agent across the blood-brain barrier of an animal, comprising administering to said animal a conjugate comprising said agent conjugated to a Receptor Associated Protein (RAP) polypeptide consisting of an amino acid sequence at least 80% identical to amino acids 221-323 of RAP (SEQ ID NO: 1), wherein said agent is transcytosed across the blood-brain barrier.
3. A method of treating a disorder of the CNS in a mammal comprising administering to said mammal a conjugate comprising an effective amount of a therapeutic agent conjugated to a Receptor Associated Protein (RAP) polypeptide consisting of an amino acid sequence at least 80% identical to amino acids 221-323 of RAP (SEQ ID NO: 1).
4. The method of claim 3 wherein said disorder is selected from the group consisting of Huntington's Disease, Alzheimer's Disease, Parkinson's Disease, Multiple Sclerosis, Amylotrophic Lateral Sclerosis, isehemia-related disease and stroke, spinal muscular atrophy, cerebellar degeneration, perivenous encephalitis, schizophrenia, epilepsy and a central nervous system cancer.
5. The method of claim 4 wherein said disorder is a central nervous system cancer and said agent is a cancer chemotherapeutic agent.
6. The method of claim 1 or 2 wherein the animal is a human.
7. The method of claim 6 wherein the human is suffering from a disorder selected from the group consisting of Huntington's Disease, Alzheimer's Disease, Parkinsonts Disease, Multiple Sclerosis, Amylotrophic Lateral Sclerosis, ischemia-related disease and stroke, spinal muscular atrophy, cerebellar degeneration, perivenous encephalitis, schizophrenia, epilepsy and a central nervous system cancer.
8. The method of claim 1 or 2 wherein the agent is a neurotrophic factor.
9. The method of claim 1 or 2 wherein the therapeutic agent is a neurotrophic factor selected from the group consisting of Glial-Derived Neurotrophic Factor, Nerve Growth Factor, Brain-Derived Neurotrophic Factor, Neurotrophin-3, Neurotrophin-4/5, aFGF, bFGF, CNTF, Leukemia Inhibitory Factor, Cardiotrophin- 1, TGFβ, BMPs, GDFs, Neurturin, Artemin, Persephin, EGF, TGFα, Neuregulins, IGF-1, IGF-2, ADNF and PDGF.
10. The method of claim 1 or 2 wherein the therapeutic agent is brain-derived neurotrophic factor (BDNF).
11. The method of any one of claims 1 to 3 wherein the polypeptide is at least 85% identical to amino acids 221-323 of RAP (SEQ ID NO: 1).
12. The method of any one of claims 1 to 3 wherein the polypeptide is at least 90% identical to amino acids 221-323 of RAP (SEQ ID NO: 1).