Targeting efferocytosis in atherosclerosis

Nick Leeper, MDProfessor of Surgery (Vascular) and Medicine (Cardiovascular)Chief, Vascular Medicine

Speaker name: Nick Leeper

..........................................................................................

I have the following potential conflicts of interest to report:

Consulting

Employment in industry

Stockholder of a healthcare company

Owner of a healthcare company

Other(s)

I do not have any potential conflict of interest

Disclosure

Munich Vascular Conference (MAC) 2019 2

The genetics of cardiovascular disease

Cardiovascular disease

The leading killer, in the US and worldwide

Great progress… but diminishing returns

Nabel EG, Braunwald E. N Engl J Med 2012; 366:54-63.

Great progress… but diminishing returns

Not addressing the disease process

Diabetes Hypertension

Smoking Cholesterol

Antiplatelets Anticoagulants

Risk Factor Reduction Clot Prevention

MechanicalStents

- Metformin- Avandia- Insulin

- Beta Blockers- Ace inhibitors- Diuretics

- Nicotine patches - Lipitor- Crestor- Niacin- PCSK9

- Bare metal stents- Drug-eluting stents

- Aspirin- Plavix

- Heparin- Coumadin

HOW DO WE GET AT THE ‘HIDDEN RISK’?

Investigating the ‘hidden risk’

Investigating the ‘hidden risk’

GWAS in cardiovascular disease

McPherson R, et al. Science, 2007. Samani NJ, et al. NEJM, 2007. Helgadottir A, et al. Science, 2007.

p < 0.000000000000018

Chromosome 9p21 is the top genetic locus

9p21 variants are very common 20% of the population is homozygous

9p21 variants are important 21% of the attributable risk for MI

9p21 variants potentiate risk independently of all classical risk factors

A 9p21 gene regulates atherosclerosis

A 9p21 gene regulates growth of the necrotic core

ApoE ControlsApoE/Cdkn2b DKO

4x

20x

10x

Hypothesis: Could 9p21 regulate “Efferocytosis”?

Latin “To Carry the Dead to the Grave”

Ravichandran KS. J Exp Med. 2010 Aug 30;207(9):1807-17.

Hypothesis: Could 9p21 regulate “Efferocytosis”?

Latin “To Carry the Dead to the Grave”

Ravichandran KS. J Exp Med. 2010 Aug 30;207(9):1807-17.

The proposed mechanism - baseline

Kojima Y, et al. JCI, 2014.Nanda V, et al. Circulation Research, 2016.

The proposed mechanism – in disease

Kojima Y, et al. JCI, 2014.Nanda V, et al. Circulation Research, 2016.

HOW DO WE TRANSLATE FROM BENCH TO BEDSIDE?

How can we stimulate efferocytosis in vivo?

Tabas I. Nat Med, 2011.

Balancing “eat-me” and “don’t-eat-me” signals

ARE ‘DON’T-EAT-ME’ MOLECULES PRESENT IN ATHEROSCLEROSIS?

CD47 is expressed at low levels in vascular tissue

But is upregulated in human atherosclerotic plaque

Swedish/German Collaborators: Ulf Hedin, Ljubica Perisic, Lars Maegdefessel

Mechanism

CAN WE TARGET THIS PROCESS, IN VIVO?

Targeting efferocytosis therapeutically Remarkable success in the oncology field

PNAS 2013, Science 2013, Science Translational Medicine 2011.

Targeting efferocytosis therapeutically

Cell 2009, PNAS 2013, Science 2013, STM 2011, Science 2015.

WILL WE HAVE THE SAME LUCK IN ATHEROSCLEROSIS?

anti-CD47 Ab increases the phagocytic index, in vivo

anti-CD47 Ab induces regression of the necrotic core

anti-CD47 Ab potently reduces atherosclerosis

anti-CD47 Ab prevents plaque rupture

Atherosclerosis at baseline

Kojima et al. Nature, 2016. Betancur et al. Nature Communications, 2017.Kojima et al. Circulation, 2017. Kojima et al. Circulation, 2018.

With efferocytosis stimulated

Kojima et al. Nature, 2016. Betancur et al. Nature Communications, 2017.Kojima et al. Circulation, 2017. Kojima et al. Circulation, 2018.

MOVING FROM BENCH TO BEDSIDE

Human cancer trials underway

With tantalizing early results

NEJM 2018, JCO 2019.

Some anemia in humans

Advani R. NEJM, 2018.

CIRCUMVENTING TOXICITY WITH ‘PRECISION’ MEDICINE

Can we block the CD47 axis specificallyin the lesional macrophage?

Macrophage-specific nanoparticles

Smith B, et al. Nature Nanotechnology. 2014

These nanoparticles accumulate in macrophage rich tumors

These nanoparticles also accumulate in lesional macrophages

‘Trojan Horse’ nanoparticles

PBS

SWNTVehicle

DAPI / Phospho-SHP-1

Pro-efferocytic SWNTs prevent atherosclerosis

Pro-efferocytic SWNTs have no toxicities

Trojan horse nanoparticles

Flores et al. Nature Nanotechnology, In Press.

Conclusions

Cardiovascular disease remains the worlds leading killer We need new orthogonal targets

Human genetics can provide powerful insights Efferocytosis as a novel target

Pro-efferocytic therapies appear to be stabilize or reverse several aspects of vascular disease Translational success will require more specific

targeting based on precision therapy approaches

Acknowledgements

Funding Sources: NIH R35 HL144475, R01 HL12522401, R01 HL12337001, AHA Established Investigator Award, Fondation Leducq‘Plaquomics’, The Falk Foundation Catalyst Award, The Greathouse Family Foundation, The Johnson Family Foundation Fund

Collaborating Labs: Weissman, Owens, Maegdefessel, Ingelsson, Smith