The purpose of this study is to identify the causes of asthma that were not previously
suspected, to better understand the effects of inhaled steroids on asthma and to identify
new way to treat asthma. In order to take advantage of the most current scientific
expertise, we (scientists at UCSF) plan to work together with Genentech Inc. We believe that
working with Genentech will provide the best chance of developing new treatments for asthma.
Asthma is a common airway disease with persistent unmet needs on terms of treatment.
Although many asthmatics enjoy good control of their disease by using regularly scheduled
corticosteroid treatment, a significant minority do not achieve optimal control with
steroids and suffer asthma exacerbations which can be severe and even fatal. Asthma
pathophysiology is complex and involves multiple cell types and multiple signaling
mechanisms. One approach to this complexity has been to study responses of isolated airway
cells to experimental conditions which model asthmatic inflammation; another has been
genetic manipulations of candidate mediators of asthma in inbred mice. These studies have
yielded important insights about possible mechanisms of asthma in humans, but the relevance
of these mechanisms to human disease has not always been proven, and it is possible that
unsuspected mechanism have not yet been revealed by these approaches.
In the studies proposed here we will
take an experimental approach which takes advantage of the distinct clinical phenotype of
human asthma, the ability to measure steroid response in asthma, the relative ease of
collecting airway cells and tissues by bronchoscopy, and the availability of new
technologies such as high density microarrays which have probes for all genes in the genome
or proteomics which can identify all proteins present in a biologic sample. Using this
approach, we will identify differential expression of genes and proteins in airway cells and
tissues in asthma that can then be explored further in cell and animal model systems to
determine their potential as drug targets in asthma. We further believe that our approach
will identify previously unsuspected mechanisms of action of corticosteroids in airway cells
and tissues in asthma. Presently, relatively little is known about why some asthmatics
respond well and some poorly to steroids and closing this gap in knowledge will help
identify candidate genes and proteins to target in order to address unmet therapeutic needs
in asthmatics with steroid resistant asthma.
- Male and female subjects between the ages of 18 and 70 years
- History of asthma
- Continuous treatment with inhaled corticosteroids for at least the 6-week
- Hyperreactivity to methacholine (PC20FEV1 Methacholine ≤ 16.0 mg/mL).
- History of asthma
- No use of oral or inhaled corticosteroids for the treatment of asthma in the past 6
- Hyperreactivity to methacholine (PC20FEV1 Methacholine ≤ 8.0 mg/mL).
- At least one of the following symptoms, beta agonist use, or FEV1 criteria:
- Asthma symptoms on at least two days per week; OR
- Beta agonist use on at least two days per week; OR
- FEV1 < 85% predicted
- Subjects must be non-smokers (patients who have never smoked or patients who have not
smoked for 1 year and have a total pack-year smoking history < 15 packs).
John V Fahy, M.D., M.Sc.
University of California, San Francisco