Novel Therapeutic Approaches for Brain AVMs UCSF Stroke and - - PowerPoint PPT Presentation

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Novel Therapeutic Approaches for Brain AVMs UCSF Stroke and - - PowerPoint PPT Presentation

9/7/2013 Novel Therapeutic Approaches for Brain AVMs UCSF Stroke and Aneurysm Update CME Saturday September 7, 2013 1:00 PM Hua Su, MD. Associate Professor Center for Cerebrovascular Research Department of Anesthesia and Perioperative Care


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CCR UCSF center for cerebrovascular research

Novel Therapeutic Approaches for Brain AVMs

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

Hua Su, MD. Associate Professor Center for Cerebrovascular Research Department of Anesthesia and Perioperative Care University of California, San Francisco Hua.su@ucsf.edu

CCR UCSF center for cerebrovascular research

Dedicated to Bill

CCR UCSF center for cerebrovascular research

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

CCR UCSF center for cerebrovascular research

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 decreased over time,

treatment of brain AVM remains associated with considerable risks and incomplete efficacy. Randomized controlled trials comparing different treatment modalities

appear justified.

Current Treatments

Surgery, embolization and radiosurgery No specific medical therapy for brain AVM

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A Randomized trial of UNRUPTURED Brain Arteriovenous Malformations NIH/NINDS Grant 1UO1 NS051483 JP Mohr, AJ Moskowitz, C Stapf Best Possible vs. Deferred Invasive Treatment for those deemed suitable for eradication Randomization 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.

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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.

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Identify Specific Targets

  • Analyzing surgical specimens
  • Modeling brain AVM in animals

CCR UCSF center for cerebrovascular research

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, 2005 Sure, Neurosurgery 55: 663, 2004 Sonstein; J Neurosurg 85:838, 1996 ZhuGe, Q. et al. Brain 2009 Murphy, PA. Laboratory Investigation 2009 Tissue assays of surgical specimens: “angiogenesis run amok” “a healing wound”

endothelium

aVB3 Ki-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

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  • 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 AVM Lung AVM Brain AVMs CCR UCSF center for cerebrovascular research

AdCre – Regional Conditional Deletion of Alk1

loxp loxp

CMV Promoter Cre recombinase Promoter Promoter

loxp

AdCre Exons 4, 5, 6 Exon 3 Exon 7 Exon 3 Alk 1 gene Exons 4,5,6 are deleted from Alk1 genome Exon 7

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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-/- only Alk1-/- /VEGF

VEGF Stimulation is Necessary for Brain AVM Formation

Alk1+/+/VEGF

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

Macrophage Infiltration

Chen et al. ATVB, 2013

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Microhemorrhage

Chen et al. ATVB, 2013

CCR UCSF center for cerebrovascular research

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

1 2 3 4 5 Pdgfb mRNA Fold Change

Control shAlk1 VEGF 0 10 50 100 (ng /ml)

* * *

0.5 1 1.5 2 2.5 3

Alk1 mRNA Fold Change

Control shAlk1

A

VEGF 0 10 50 100

(ng /ml)

* * * *

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ALK1 knockdown in HBMEC impairs the pericyte recruitment

20 40 60 VEGF + shAlk1 shAlk1 VEGF Control Average Pericyte Distance µm

A B

* *

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50 µm

Gene Mutation in Bone Marrow Transmits the Phenotype

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Potential Therapies for Brain AVMs

  • 1. Anti-inflammation: Minocycline
  • 2. Anti-angiogenesis: Avastin, sFLT
  • 3. Increase PDGFB, improve vessel integrity

Thalidomide

  • 4. Bone marrow transplantation

Peripheral monocyte/progenitor transfusion

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Lee, C. Z. et al. Stroke 2004

Anti-Inflammation

Doxycycline Treatment Reduces Angiogenesis in VEGF Treated Mouse Brain

CCR UCSF center for cerebrovascular research

Anti-Angiogenesis

Bevacizumab reverse brain AVM phenotype

Walker et al. Stroke, 2012 CCR UCSF center for cerebrovascular research

Anti-Angiogenesis

Stereotactic Injection of AAV2-sFLT Inhibited Brain AVM Formation

Control Treated

CCR UCSF center for cerebrovascular research

Anti-Angiogenesis

Systemic Delivery of AAV9-sFLT Inhibited the Brain AVM Formation

Control Treated

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CCR UCSF center for cerebrovascular research

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

Increase PDGFB

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Increase PDGFB

Thalidomide Treatment Reduced the Number of Abnormal Vessels

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Increase PDGFB

Thalidomide Treatment Reduced Microhemorrhage

CCR UCSF center for cerebrovascular research

Summary

  • 1. Invasive therapies are associated with considerable risks
  • 2. No specific medical therapy is available
  • 3. 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-inflammation
  • B. Anti-angiogenesis
  • C. Improve vascular integrity
  • D. 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 / NINDS NIH / ORDR AHA Lesle Monzer Fundation Michael Ryan Zodda Fundation avm ucsf