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LeadDiscovery Reports
The involvement of PDE4D in stroke
Of the 11 phosphodiesterase
subtypes that have been identified, drug development activity has centered on
two subtypes, PDE4 and PDE5. PDE4 has been targeted for the treatment of
inflammation, and in particular asthma and chronic obstructive disorder (COPD;
emphysema & bronchitis).
Over recent years a number of major advances have been made with respect to
PDE4 inhibition. Early proof of concept studies strongly favored the use of
PDE4 inhibitors for the treatment of COPD and asthma and indeed airway
inflammation represents the primary indication for this drug class (click
here for a full analysis of emerging asthma targets and therapeutics). Of
the selective PDE4 inhibitors, Cilomilast and Roflumilast have been the most
advanced.
In addition to advances in the development of PDE4 inhibitors for the
treatment of airway disorders, new indication for this therapeutic class are
also emerging. LeadDiscovery's forthcoming state of the art, "PDE4 & PDE5:
Pharmaceutical advances and new therapeutic target" (click
here for details) analyses advances in PDE therapeutics as well as new
indications. One such new indication is stroke, which has been linked to both
of these phosphodiesterase subtypes.
Stroke represents a largely unmet market; 600,000 individuals suffer a stroke
in the US each year and more than 160,000 die from stroke-related causes.
Patients that present more than 3 hours after the onset of symptoms are
particularly difficult to treat since neural cell death becomes a major
problem as do the neurological consequences of synaptic loss. Ischemic stroke
which accounts for 80-90% of strokes can be sub-divided into large vessel
occlusive disease (carotid stroke) which is commonly due to atherosclerosis of
the common and internal carotid arteries; small vessel occlusive disease due
to non-atherosclerotic narrowing of small end-arteries in the brain; and
cardiogenic stroke due to blood clots arising from the heart.
The Icelandic biotech deCode have recently published ground breaking data
linking PDE4D (one of four PDE4 isoforms which exists in multiple splice
variants) with stroke, which has long been know to have genetic component. In
their recent Nature Genetics paper Gretarsdottir et al report on a positional
cloning study of the STRK1 locus which was identified as a stroke
susceptibility locus in 2002. Two groups of Icelandic individuals comprised of
908 control and 864 stroke affected patients were genotyped using 98
microsatellite markers across the STRK1 locus. When the patient group was
subdivided into those with cardiogenic stroke, carotid stroke or both, one
marker was identified in cardiogenic stroke patients; another in carotid
stroke patients. These markers were located within the 5’ end of the PDE4 gene
and within the PDE4 gene respectively. Analyzing single nucleotide
polymorphisms confirmed this finding. The polymorphisms identified in the
stroke patient groups were suggested to be in regions flanking exons rather
than in the exons themselves, and in particular exons D7-1 and D7-2. Hence
polymorphisms are likely to affect PDE4 gene transcription, splicing, message
stability or message transport in stroke patients.
Based on linkage analysis, haplotypes were defined, each of which carried
different risks for cardiogenic and carotid stroke. Haplotypes covering the
first exon of PDE4 (D7-1) can be classified into three groups associated with
different risks; at risk; wild type and protected. Approximately 16% and 0.8%
of the general population was calculated to carry one and two copies of the
at-risk haplotype respectively. These individuals were estimated to be 1.8 and
3.8 times more at risk than the general population of suffering a cardiogenic
or carotid stroke. The so-called at-risk haplotypes were characterized by a
lower expression of PDE4D7 and PDE4D9.
High levels of cAMP are generally considered to be consistent with
anti-inflammatory activity and reduced vascular smooth muscle proliferation.
Furthermore inhibitors of PDE4 are able to counter the inflammatory properties
of macrophage and relax vascular smooth muscle suggesting that reduced levels
of PDE4 isoforms or their pharmacological inhibition would confer protection
against stroke. The current study therefore yields what may at first appear
paradoxical data since PDE4D7 and PDE4D9 expression is reduced in patients
with increased risk of stroke. One possible explanation of this paradox is
that cAMP itself is able to increase the expression of PDE4D isoforms and the
under-expression of PDE4D7 and PDE4D9 may be indicative of defects in cAMP
generation. The development of PDE inhibitors that increase cAMP levels and
which can correct the defect in PDE4D7 and PDE4D9 expression may therefore be
of benefit for the treatment of stroke. Thus future studies that focus on the
regulation of the expression of these isoforms are eagerly awaited.
Entry date Wednesday, November 12, 2003
Adapted from Gretarsdottir et al, Nat Genet. 2003 Oct;35(2):131-8.
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