Novel Therapeutic Approaches for Brain AVMs...Bevacizumab reverse brain AVM phenotype Walker et al....
Transcript of Novel Therapeutic Approaches for Brain AVMs...Bevacizumab reverse brain AVM phenotype Walker et al....
9/7/2013
1
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]
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 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
9/7/2013
2
CCR UCSF center for cerebrovascular research
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.
CCR UCSF center for cerebrovascular research
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, 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
9/7/2013
3
CCR UCSF center for cerebrovascular research
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
CCR UCSF center for cerebrovascular research
• 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
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, 6Exo
n 3
Exo
n 7
Exo
n 3
Alk 1 gene
Exons 4,5,6 are deleted from Alk1 genome
Exo
n 7
CCR UCSF center for cerebrovascular research
Alk1 Regional Conditional Deletion Plus VEGF Stimulation Results in Brain AVM
AdCre + AAV-VEGF
8 wks
Alk1 -/-
Angiogenesis
Walker et al. Ann Neurology, 2011
9/7/2013
4
CCR UCSF center for cerebrovascular research
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
CCR UCSF center for cerebrovascular research
Microhemorrhage
Chen et al. ATVB, 2013
CCR UCSF center for cerebrovascular research
PDGFB Signaling Regulates Smooth Muscle Recruitment
Hellstrom; Development, 1999
9/7/2013
5
CCR UCSF center for cerebrovascular research
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)
* * * *
CCR UCSF center for cerebrovascular research
ALK1 knockdown in HBMEC impairs the pericyte recruitment
20 40 60
VEGF + shAlk1
shAlk1
VEGF
Control
Average Pericyte Distance µm
A B
**
CCR UCSF center for cerebrovascular research
50 µm
Gene Mutation in Bone Marrow Transmits the Phenotype
CCR UCSF center for cerebrovascular research
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
9/7/2013
6
CCR UCSF center for cerebrovascular research Lee, C. Z. et al. Stroke 2004
Anti-InflammationDoxycycline Treatment Reduces Angiogenesis in
VEGF Treated Mouse Brain
CCR UCSF center for cerebrovascular research
Anti-AngiogenesisBevacizumab reverse brain AVM phenotype
Walker et al. Stroke, 2012
CCR UCSF center for cerebrovascular research
Anti-AngiogenesisStereotactic 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
9/7/2013
7
CCR UCSF center for cerebrovascular research
Lebrin, et al, Nat Med 16: 420, 2010
Increase PDGFB
CCR UCSF center for cerebrovascular research
Increase PDGFB Thalidomide Treatment Reduced the Number of Abnormal Vessels
CCR UCSF center for cerebrovascular research
Increase PDGFB Thalidomide Treatment Reduced Microhemorrhage
CCR UCSF center for cerebrovascular research
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
9/7/2013
8
CCR UCSF center for cerebrovascular research
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