Therapies aimed at treating disease symptoms is what is currently done in clinics worldwide. Antibiotics treat infection,
Pulmozyme (recombinant DNase) treats the thickened lung mucus, anti-inflammatory
agents treat lung inflammation, and so forth. Many new ‘symptom-based’
therapies are in the development pipeline.
For therapies
aimed at treating the underlying lung disease to be effective,
improved understanding of how lung disease develops in cystic
fibrosis is essential |
Therapies aimed at treating underlying lung
problems require a clear understanding of how defective
CFTR function causes lung disease, which is still an unresolved problem
of intense research. One theory proposes that sodium is excessively
absorbed in the lung in cystic fibrosis, which produces a thickened
mucus. Blocking sodium absorption has therefore been proposed as one
type of therapy. Abnormal secretion by fluid-producing glands in the
airways in cystic fibrosis is another theory of how lung disease develops
in cystic fibrosis. Yet other theories have been proposed such as excessive
inflammation in cystic fibrosis causing the lung disease, and reduced
ability of the lung to kill bacterial. For therapies aimed at treating
the underlying lung disease to be effective, improved understanding
of how lung disease develops in cystic fibrosis is essential. At present
there are no therapies for cystic fibrosis aimed at treating the cause
of lung disease, though such drugs are in the development pipeline and
may soon be available.
A promising
approach for treating the underlying CFTR defect is to discover
drugs that improve the function of the abnormal CFTR protein in
cystic fibrosis |
The third category of therapy – treating the underlying
CFTR defect – is potentially the most exciting and promising.
Gene therapy is one such therapy aimed at replacing the defective CFTR
gene with the normal gene. However, effective gene therapy for cystic
fibrosis remains a long-term prospect, as research over the past decade
has identified many significant hurdles to be overcome. For example,
it is difficult to efficiently and safely deliver normal genes to the
airways, as well as to repeatedly administer the therapy without immune
and other effects.
The other approach for treating the underlying CFTR defect
is to discover drugs that improve the function of the abnormal CFTR
protein in cystic fibrosis. The ΔF508
mutation in CFTR is the most common cause of cystic fibrosis worldwide,
with at least one copy of the ΔF508-CFTR
gene being present in around 90% of subjects. A drug that could ‘rescue’
the ΔF508-CFTR
protein would be ideal since it would target the cells that normally
express CFTR. Our lab has been working for the last five years on the
discovery of drugs to rescue the ΔF508-CFTR
protein.
A robotic
device in needed because the screening of many compounds is extremely
labor intensive and must be done with great accuracy. |
How are new drugs discovered? The most commonly used strategy
is called ‘high-throughput screening’ (HTS), whereby up
to millions of diverse chemicals are screened by a robotic device as
the one in our laboratory shown in Figure 1. Usually the chemicals consist
of collections of artificially synthesized small molecules, though sometimes
natural compounds such as herb extracts are screened. A robotic device
in needed because the screening of many compounds is extremely labor
intensive and must be done with great accuracy. To screen for drugs
that rescue the abnormal function of ΔF508-CFTR,
we developed a fluorescence method that measures CFTR chloride channel
function. The basic assay involved testing compounds for their ability
to restore CFTR function in cells containing the ΔF508-CFTR
protein.
By screening
more than 150,000 chemicals, we have discovered several classes
of small, drug-like chemicals that are able to correct the defects
in cystic fibrosis cells, making the cystic fibrosis cell look
more like the normal cell. |
The initial results are very promising. (Technical details
of the findings can be read in the two papers cited at the end of this
article.) It turns out that the ΔF508
mutation causes at least two defects in the CFTR protein (see Figure
2). One defect is that its ‘gating’, or ability to transport
chloride, is reduced compared to normal CFTR. The other defect is that
its cellular processing is abnormal – the ΔF508-CFTR
protein remains inside the cell rather than reaching the cell surface
as it should. By screening more than 150,000 chemicals, we have discovered
several classes of small, drug-like chemicals that are able to correct
each of these defects, making the cystic fibrosis cell look more like
the normal cell.
However, it is a long way from initial discovery of potentially
useful compounds to their use in treating a disease. Before initial
phase 1 testing in humans, much work is needed to evaluate the toxicity
and pharmacology of new drugs. Even after human studies begin, at least
6-7 years is generally needed before a compound is approved for general
use (outside of clinical trials). Also, most compounds that enter clinical
trials are not ultimately approved because of toxicity, lack of effectiveness,
and other problems.
Nonetheless,
this is a very exciting time in cystic fibrosis research, since
for the first time drug candidates are emerging that treat the
underlying CFTR defect. |
Further reading:
1) Verkman, A.S. (2004). Drug discovery in academia. American Journal
of Physiology 286:C465-C474.
Editor: to get online access
to the article above, go to:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=pubmed
2) Pedemonte, N., G.L. Lukacs, K. Du, E. Caci, O. Zegarra-Moran,
L.J. Galietta and A.S. Verkman (2005). Small molecule correctors of
defective ΔF508-CFTR
cellular processing identified by high-throughput screening. Journal
of Clinical Investigation. To be published August, 2005.
