Transcript CUMC – CEA DATA

Gene Therapy for Vascular
Disease - State of the Art ?
K. Craig Kent M.D.
Angiogenesis
for
lower extremity vascular disease
Angiogenesis
Arteriogenesis
Angiogenic Growth Factors
• Vascular Endothelial Growth Factor (VEGF)
• Fibroblast Growth Factor (FGF)
• Hepatocyte growth Factor (HGF)
Insulin-like growth factor
Granulocyte colony stimulating factor
Hypoxia inducible factor
Kallikrein
Angiopoietin
Transforming growth factor
Therapeutic
Angiogenesis
Clinical Trials
Conclusion
Potential is tremendous !
Many new innovations !
Another few years away !
Application of Angiogenic Therapy
Form
* Protein
* DNA
Viral
Naked
Route
* Intravenous
* Intraarterial
* Intramuscular
Clinical Trials - angiogenesis
•
•
•
•
•
Isner et. al.
NYPH
TRAFFIC
AVENTIS
TACT
Therapeutic Angiogenesis for Lower Extremity Ischemia
New York Presbyterian Hospital
FDA approved Phase 1 double blinded placebo
controlled clinical trial
Growth factor - VEGF 121
Form - Replication deficient adenovirus
Route - Intramuscular injections
Ascending dosing schedule, 4 x 108 - 4 x 1010 pfus
New York Presbyterian Hospital
Claudication - 20 Patients
Limb Threat - 20 Patients
New York Presbyterian Hospital
Results
• No adverse events: adenoviral VEGF is safe
• No statistically signficant benefit in either group
(TRAFFIC) Therapeutic Angiogenesis with FGF-2
(protein) For Intermittent Claudication
• Growth factor - recombinant FGF-2
• Form - protein
• Route - Intraarterial
Phase II, multicenter, randomized, double blind, placebo
controlled trial
Intermittent claudication
TRAFFIC
METHODS
Patients:
190
Inclusion: Claudication, ABI < 0.8
Route:
Groups:
Intra-arterial
Group # 1
Group # 2
Group # 3
Day 0
Placebo
FGF
FGF
Day 30
Placebo
Placebo
FGF
TRAFFIC
Primary Endpoint
Peak walking time
Secondary Endpoints
Claudication onset time
Ankle brachial index
Quality of life
Results - Primary Endpoint
Peak Walking Time (90 days)
35%
p= 0.026
30%
1.77 min
25%
20%
1.54 min
.6 min
15%
10%
5%
0%
Placebo
Single dose
Double dose
Secondary Endpoint
Change in peak walking time at 180 days
2
1.8
1.6
1.4
Change in 1.2
PWT
1
(minutes) 0.8
0.6
0.4
0.2
0
Placebo
p=N.S
DAY 180
Single dose Double dose
Secondary Endpoints
No difference at 90 or 180 days
• Claudication onset time
• Quality of life
Walking impairment questionnaire and SF-36
Traffic: Conclusions
• Intra-arterial infusion of rFGF-2 is safe
(albeit hypotension and proteinuria were observed)
• Statistically significant increase in PWT
at 90 days
• Clinical relevance - unlikely
Aventis - Phase I Trial
Comerota et al.
• Growth factor - FGF
• Form - naked DNA
• Route - Intramuscular
Phase I, multicenter nonrandomized trial
limb threatening ischemia
Aventis - Phase I
METHODS
• Patients: n=51.
• Inclusion: Ischemic rest pain, ABI < 0.4
• Dosage: 500, 1000, 2000, 4000 ug NV1FGF
Aventis - Phase I
Results - Safety
• No serious adverse events attributable to FGF
• No pathological angiogenesis
Results
***
**
1
2
3
7
11
23
**p=.007
***p=.005
Results
***
**
*
1
*
2
*
3
7
23
* p<.03
** p=.001
***p=.0001
Results
*
**
1
2
3
7
**
11
**
23
*p=.04
**p=.0001
Results
*
P < .01
1
2
3
7 11 23
Aventis phase I trial
Limitations:
• Number of patients small (n =15@ 6 mo)
• No randomization
phase 2 is now completed - awaiting results
Stem Cells
(Endothelial Progenitor Cells)
Angiogenesis
Bone Marrow
Endothelial
Progenitor
Cell
Peripheral Blood
Ischemic Tissue
Capillary
formation
VEGF
FGF
cytokines
TACT Investigators (therapeutic angiogenesis using
cell transplantation)
Lancet - August 2002
Methods:
• Bone marrow aspirate (500 cc)
• Monocytes isolated and concentrated into (30 cc)
• Injection into the gastrocnemius muscle (3 hrs)
40 injections
26 gauge needle
1.5 cm deep
0.75cc each
TACT
Results
Total legs injected = 45
weeks
0
4
16
ABI
.35
.42
.46
TcO2(mm Hg)
28
46
45
Pain free (min)
walking time
1.3
3.6
3.7
TACT
Results
Total legs injected = 45
Relief of rest pain
complete 22
partial 15
Prevention of toe amputation
15/20
Improvement of ischemic ulceration
6/10
Increase in collaterals by angiography
27/45
Stem cell therapy for
angiogenesis
is the new frontier
Unknown
Where to Inject ?
How deep
How many
Unknown
Protein ?
Naked DNA ?
Viral Vector ?
Stem cells ?
Unknown
Concentration of protein,
DNA or stem cells ?
Unknown
Does it work ?