intro-to-tager-lab - Second Wind Foundation for Pulmonary Fibrosis

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MGH Research in IPF:
Identifying New Targets for
Effective Drug Therapies
Andrew M. Tager, M.D.
Interstitial Lung Disease Program
Pulmonary and Critical Care Unit
Massachusetts General Hospital
Harvard Medical School
Unmet Need for Effective IPF Therapy
• US demographics:
Incidence > 30,000 patients / year
Prevalence > 80,000 current patients
• Poor prognosis:
35.2
mos
Conventional Treatment of IPF
• Recommendation of 2000 ATS / ERS consensus statement
Prednisone
+
0.5 mg/kg/d x 4 wks
then
0.25 mg/kg/d x 8 wks
then
0.125 mg/kg/d
or
0.25 mg/kg QOD
Azathrioprine
2 - 3 mg/kg/d
(150 mg/d max)
Start at 25 - 50 mg/d
 by 25 mg q 7 - 14 d
or
Cyclophosphamide
2 mg/kg/d
(150 mg/d max)
Start at 25 - 50 mg/d
 by 25 mg q 7 - 14 d
• Recommendation based on hypothesis that IPF
results from chronic inflammation
• There are lung diseases where chronic inflammation
causes fibrosis, such as hypersensitivity pneumonitis
PANTHER Trial of Conventional Treatment of IPF
(Prednisone / Azathioprine / NAC)
Treatment Arms: Pred / Aza / NAC - vs - NAC alone - vs - Placebo
Conventional IPF Treatment Lacks Efficacy
Injury / Abnormal Repair
Hypothesis of IPF Pathogenesis
• IPF pathology suggests:
repetitive / recurrent injury
Effective repair
Restoration of normal
structure and function
Ineffective repair
Pulmonary fibrosis
and loss of function
• What injures the lung in IPF?
– Unknown / may be different in different patients
• Why are repair responses ineffective in IPF?
– Recurrent nature of injury may overwhelm repair mechanisms
– Repair mechanisms may be abnormal / overly exuberant
Phases of Wound Healing Responses to Injury
Epithelium
Lung Injury
Capillary
Basement
Membrane
Epithelial
Cell Death
Vascular leak
Re-epithelialization
Fibroblast Accumulation
Fibrin Clot
Extracellular
Matrix
and
Matrix Deposition
Fibroblasts
Abnormalities of any of these responses can contribute to fibrosis
BAL from IPF Patients Contains
Signals that Attract Fibroblasts
• The amount of these signals present in BAL correlates with
IPF severity and rate of progression
• These fibroblast-attracting signals are also present in mouse
models of pulmonary fibrosis
BAL from normal mouse
BAL from mouse with
pulmonary fibrosis
Discovery of LPA as the Signal that
Attracts Fibroblasts to the Lung in IPF
• We discovered LPA by purifying the fibroblast attractant
activity in BAL
• LPA exerts its effects through several molecules on the
surface of cells called receptors
• We discovered that LPA exerts its pro-fibrotic effects through
one of these receptors, called LPA1
• We demonstrated the importance of the LPA-LPA1 pathway
to lung fibrosis with mice genetically lacking LPA1
− LPA1 knockout mice (LPA1 KOs)
Bleomycin-induced Fibrosis Requires LPA1
Normal mouse after bleomycin
Mouse lung – normal appearance
LPA1 KO mouse after bleomycin
Bleomycin-induced Fibrosis Requires LPA1
100
Percent survival
LPA1 KO
75
50
Normal mice
25
0
0
5
10
15
Days post challenge
20
Bringing LPA-LPA1 Pathway Inhibition
to the Clinic
Bringing LPA-LPA1 Pathway Inhibition
to the Clinic
LPA-LPA1 Pathway Inhibition:
an Academic-Industry Collaboration
Target Discovery
IPF Patients
Drug Discovery
Clinical Trials
THANK YOU
SECOND WIND
FOUNDATION!!!!!
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