novel therapeutic approaches for brain avms...bevacizumab reverse brain avm phenotype walker et al....

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CCR UCSF center for cerebrovascular research

Novel Therapeutic Approaches for Brain AVMs

UCSF Stroke and Aneurysm Update CMESaturday September 7, 2013 1:00 PM

Hua Su, MD. Associate Professor

Center for Cerebrovascular ResearchDepartment of Anesthesia and Perioperative Care

University of California, San [email protected]


Dedicated to Bill


Brain Arteriovenous Malformations (AVMs)

Yamada, in Cerebral Blood Flow; McGraw-Hill, 1987

•Tangle of abnormal blood vessels (nidus) –No intranidal capillary bed–arteriovenous shunting–Range of vessel types

• Located randomly throughout brain• Cause of hemorrhagic stroke


Outcomes following treatment of brain arteriovenous malformations (AVMs) with microsurgery, embolization, stereotactic radiosurgery (SRS), or combinations vary greatly between studies.

Outcomes following treatment of brain arteriovenous malformations (AVMs) with microsurgery, embolization, stereotactic radiosurgery (SRS), or combinations vary greatly between studies. Case fatality was 0.68 (95% CI, 0.61-0.76) per 100 person-years overall, 1.1 (95% CI, 0.87-1.3; n = 2549) after microsurgery, 0.50 (95% CI, 0.43-0.58; n = 9436) after SRS, and 0.96 (95% CI, 0.67-1.4; n = 1019) after embolization. Intracranial hemorrhage rates were 1.4 (95% CI, 1.3-1.5) per 100 person-years overall, 0.18 (95% CI, 0.10-0.30) after microsurgery, 1.7 (95% CI, 1.5-1.8) after SRS, and 1.7 (95% CI, 1.3-2.3) after embolization. More recent studies were associated with lower case-fatality rates (rate ratio [RR], 0.972; 95% CI, 0.955-0.989) but increased rates of hemorrhage (RR, 1.02; 95% CI, 1.00-1.03). CONCLUSIONS: Although case fatality after treatment has decrease d over time, treatment of brain AVM remains associated with cons iderable risks and incomplete efficacy . Randomized controlled trials comparing different treatment modalities appear justified.

Current TreatmentsSurgery, embolization and radiosurgery

No specific medical therapy for brain AVM

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A Randomized trial of UNRUPTURED Brain Arteriovenous MalformationsNIH/NINDS Grant 1UO1 NS051483

JP Mohr, AJ Moskowitz, C StapfBest Possible vs. Deferred Invasive Treatment

for those deemed suitable for eradicationRandomization plan 1:1 = 400 cases

Comparison of any invasive therapy to medical management arm (defer invasive treatment for up to 5 years).

The trial stopped early due to a huge effect in favor of the medical management arm. CCR UCSF center for cerebrovascular research

Unlike cancer-related chemotherapy that aims to shrink abnormal tumor tissue as cytotoxic therapy, the concept for the treatment of brain AVM would be to stabilize vascular tissue and thereby decrease the risk of spontaneous ICH.


Identify Specific Targets

-Analyzing surgical specimens-Modeling brain AVM in animals


Macrophage & Leukocytes

smooth muscle

VEGF

VEGF-R

MMP-9

Tie-2

Imbalance in Angiopoietin 1 & 2

astrocyte

Hashimoto, Neurosurgery 54: 410, 2004

Shenkar, Neurosurgery 52: 465, 2003 Kilic, Neurosurgery 57: 997, 2005Sure, Neurosurgery 55: 663, 2004Sonstein; J Neurosurg 85:838, 1996ZhuGe, Q. et al. Brain 2009

Murphy, PA. Laboratory Investigation 2009

Tissue assays of surgical specimens: “angiogenesis run amok”

“a healing wound”

endothelium

aVB3Ki-67

HIF-1α

Notch

Notch

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Are brain AVMs heritable?

• Familial

– Hereditary Hemorrhagic Telangiectasias (HHT)

– RASA1 (p120 RasGAP, is a Ras GTPase–activating protein) capillary malformation-AVM

• Eerola, Am J Hum Genet 73: 1240, 2003

– Non-HHT• 53 patients in 25 families

– van Beijnum, et al, JNNP 78: 1213, 2007

– Inoue, et al, Stroke 38: 1368, 2007

• Sporadic

– 95-98% no family hx


• Autosomal dominant disorder

• Mucocutaneous telangiectasia

• AVMs in Liver, Lung and Brain

• 80% of cases have functional heploinsufficiency of

Endoglin (HHT1) or ALK1 (HHT2)

Hereditary Hemorrhagic Telangiectasia (HHT)Rendu-Osler-Weber Syndrome

Liver AVMLung AVM Brain AVMs


AdCre – Regional Conditional Deletion of Alk1

loxp

loxp

CMV Promoter Cre recombinase

Promoter

Promoter

loxp

AdCre

Exons 4, 5, 6Exo

n 3

Exo

n 7

Exo

n 3

Alk 1 gene

Exons 4,5,6 are deleted from Alk1 genome

Exo

n 7


Alk1 Regional Conditional Deletion Plus VEGF Stimulation Results in Brain AVM

AdCre + AAV-VEGF

8 wks

Alk1 -/-

Angiogenesis

Walker et al. Ann Neurology, 2011

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Alk1+/+/VEGF

Alk1-/- onlyAlk1-/- /VEGF

VEGF Stimulation is Necessary for Brain AVM Formation

Alk1+/+/VEGF

Walker et al. Ann Neurology, 2011CCR UCSF center for cerebrovascular research

Macrophage Infiltration

Chen et al. ATVB, 2013


Microhemorrhage

Chen et al. ATVB, 2013


PDGFB Signaling Regulates Smooth Muscle Recruitment

Hellstrom; Development, 1999

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ALK1 Knockdown Attenuates the Upregulation of PDGFB in HBMEC in Response to VEGF Stimulation

HBMEC (human brain microvascular endothelial cell) were transfected with control shRNA or shRNA . Cells with >70% reduction of Alk1 gene expression were cultured for 18 h in the presence or absence of VEGF (0, 10, 50, and 100 ng/ml). qRT-PCR was performed for Alk1(A) and Pdgfb (B). All data are shown as mean and SD. *p<0.05 vs. control.

B

0

1

2

3

4

5

Pd

gfb

mR

NA

Fol

d C

hang

e

ControlshAlk1

VEGF 0 10 50 100(ng /ml)

**

*

0

0.5

1

1.5

2

2.5

3

Alk

1m

RN

A F

old

Cha

nge

ControlshAlk1

A

VEGF 0 10 50 100(ng /ml)

* * * *


ALK1 knockdown in HBMEC impairs the pericyte recruitment

20 40 60

VEGF + shAlk1

shAlk1

VEGF

Control

Average Pericyte Distance µm

A B

**


50 µm

Gene Mutation in Bone Marrow Transmits the Phenotype


Potential Therapies for Brain AVMs

1. Anti-inflammation: Minocycline

2. Anti-angiogenesis: Avastin, sFLT

3. Increase PDGFB, improve vessel integrityThalidomide

4. Bone marrow transplantationPeripheral monocyte/progenitor transfusion

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CCR UCSF center for cerebrovascular research Lee, C. Z. et al. Stroke 2004

Anti-InflammationDoxycycline Treatment Reduces Angiogenesis in

VEGF Treated Mouse Brain


Anti-AngiogenesisBevacizumab reverse brain AVM phenotype

Walker et al. Stroke, 2012


Anti-AngiogenesisStereotactic Injection of AAV2-sFLT Inhibited Brain AVM Formation

Control

Treated


Anti-Angiogenesis Systemic Delivery of AAV9-sFLT Inhibited the Brain AVM Formation

Control

Treated

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Lebrin, et al, Nat Med 16: 420, 2010

Increase PDGFB


Increase PDGFB Thalidomide Treatment Reduced the Number of Abnormal Vessels


Increase PDGFB Thalidomide Treatment Reduced Microhemorrhage


Summary

1. Invasive therapies are associated with considerable risks2. No specific medical therapy is available3. The concept for the treatment of brain AVM is to

stabilize vascular tissue and thereby decrease the risk of spontaneous ICH.

4. Novel therapeutic approaches: A. Anti-inflammationB. Anti-angiogenesisC. Improve vascular integrityD. Correct gene mutation in BM monocyte/progenitors

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UCSF center for cerebrovascular research

William L. Young Anesthesia , Neurosurg, Neurol

Helen Kim Anesthesia, Epi & Biostats, IHG

Hua Su Anesthesia

Ludmila Pawlikowska Anesthesia, IHG

Tomoki Hashimoto Anesthesia

Chanhung Lee Anesthesia

Nerissa U. Ko Neurology

Michael T. Lawton Neurosurgery

Charles E. McCulloch Epi & Biostats

Jonathan G. Zaroff Kaiser Cardiology

Funding:

NIH / NINDSNIH / ORDRAHA

Lesle Monzer Fundation

Michael Ryan Zodda Fundation

avm ucsf

novel therapeutic approaches for brain avms...bevacizumab reverse brain avm phenotype walker et al....

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