Modulation of efferocytosis pathways for treatment of atherosclerotic disease
Smooth muscle cells (SMC) from subjects carrying at least one 9p21 risk factor, can be resistant to efferocytosis, leading to the retention of such cells in the necrotic core of atherosclerotic plaque. In the methods of the invention, an agent that increases efferocytosis of cellular components of coronary plaque, including efferocytosis of apoptotic smooth muscle cells, is administered to the subject in a dose and for a period of time effective to stabilize, prevent or reduce atherosclerotic plaque in the individual.
1. A method of reducing atherosclerotic plaque in a human subject, the method comprising:
genotyping the subject for the presence of at least one 9p21 risk allele, where an individual determined to have a 9p21 risk allele for atherosclerosis is treated, by
administering to the subject an effective dose of an anti-CD47 polypeptide that reduces the binding of CD47 on an apoptotic cell to Signal regulatory protein alpha (SIRPα) on a phagocytic cell that increases the efferocytosis of cellular components of atherosclerotic plaque, thereby inhibiting atherosclerotic plaque.
2. The method of claim 1 , wherein the 9p21 risk allele is genotyped by determination of the presence of an single nucleotide polymorphism (SNP) variant at 9p21 associated with risk.
3. The method of claim 1 , wherein the anti-CD47 polypeptide is an antibody that specifically binds CD47.
4. The method of claim 3 , wherein the antibody is humanized 5F9-hIgG4.
5. The method of claim 3 , wherein the antibody does not activate CD47 upon binding.
6. The method of claim 1 , wherein the anti-CD47 agent is a soluble SIRPα reagent.
7. The method of claim 6 , wherein the agent is a high affinity soluble SIRPα reagent.
8. The method of claim 1 , wherein the anti-CD47 agent specifically binds SIRPα.
9. The method of claim 8 , wherein the anti-CD47 agent is an antibody.