Use of semaphorin-4D binding molecules to promote neurogenesis following stroke
Provided herein are methods for promoting neurogenesis in neural tissue of a patient exhibiting at least one symptom of a central nervous system disorder, the method comprising administering to a subject in need thereof an effective amount of an isolated binding molecule which specifically binds to semaphorin-4D (SEMA4D).
1. A method for regenerating neurons in a subject comprising administering to a subject in need of neural regeneration as a result of stroke an effective amount of an isolated antibody or an antigen-binding fragment thereof that comprises
a variable domain of a heavy chain (VH) comprising the VH-CDR1, VH-CDR2, and VH-CDR3 amino acid sequences SEQ ID NOs: 5, 6, and 7, respectively, and
a variable domain of a light chain (VL) comprising the VL-CDR1, VL-CDR2, and VL-CDR3 amino acid sequences SEQ ID NOs: 8, 9, and 10, respectively,
wherein the antibody or fragment thereof specifically binds to semaphorin-4D (SEMA4D) and
wherein the subject exhibits an increase in one or more of proliferation, differentiation, or migration of neural progenitor cells.
2. The method of claim 1 , wherein the antibody or fragment thereof is administered to the blood side of the blood brain barrier.
3. The method of claim 1 , wherein the antibody or fragment thereof is administered to the brain side of the blood brain barrier.
4. The method of claim 1 , wherein the subject exhibits an increase in differentiation of neural progenitor cells.
5. The method of claim 1 , wherein the antibody or fragment thereof comprises a VH having the sequence set forth in SEQ ID NO: 1 and a VL having the sequence set forth in SEQ ID NO: 2.
6. The method of claim 1 , wherein the antibody or fragment thereof comprises a VH having the sequence set forth in SEQ ID NO: 3 and a VL having the sequence set forth in SEQ ID NO: 4.
7. The method of claim 1 wherein the subject exhibits an increase in expression of a neural precursor or progenitor cell marker.
8. The method of claim 7 , wherein the marker is Sox2 and/or nestin.
9. The method of claim 1 , wherein the antibody or antigen-binding fragment thereof is IgG isotype.
10. A method for regenerating neurons and increasing striatal brain volume in a subject comprising administering to a subject in need of neural regeneration and increased striatal brain volume as a result of stroke an effective amount of an isolated antibody or an antigen-binding fragment thereof that comprises
a variable domain of a heavy chain (VH) comprising the VH-CDR1, VH-CDR2, and VH-CDR3 amino acid sequences SEQ ID NOs: 5, 6, and 7, respectively, and
a variable domain of a light chain (VL) comprising the VL-CDR1, VL-CDR2, and VL-CDR3 amino acid sequences SEQ ID NOs: 8, 9, and 10, respectively,
wherein the antibody or fragment thereof specifically binds to semaphorin-4D (SEMA4D) and
wherein the subject exhibits an increase in striatal brain volume and one or more of proliferation, differentiation, or migration of neural progenitor cells.