2008 Barcelona - European Society of Human Genetics

Concurrent Symposia
s02.3
small-molecule therapy for cystic Fibrosis
A. S. Verkman;
Departments of Medicine and Physiology, University of California, San Francisco,
San Francisco, CA, United States.
The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)
is a cAMP-activated chloride channel expressed in epithelia in the
lung, intestine, pancreas, testis and other tissues, where it facilitates
transepithelial fluid transport. In the intestine CFTR provides the major
route for chloride secretion in certain diarrheas . Mutations in CFTR
cause the hereditary disease cystic fibrosis, where chronic lung infection
and deterioration in lung function cause early death . CFTR is
a well-validated targeted for development of inhibitors for therapy of
secretory diarrheas and polycystic kidney disease, and activators for
therapy in cystic fibrosis. Our lab has identified and optimized small
molecule inhibitors of CFTR, as well as activators of deltaF508-CFTR,
the most common mutant CFTR causing cystic fibrosis. High-throughput
screening of small molecule collections utilizing a cell-based fluorescence
assay of halide transport yielded thiazolidinone and glycine
hydrazide CFTR inhibitors that block enterotoxin-mediated secretory
diarrhea in rodent models, including a class of non-absorbable inhibitors
that target the CFTR pore at its external entrance . Nanomolarpotency
benzothiophene, phenylglycine and sulfonamide potentiators
were identified that correct the defective gating of deltaF508-CFTR
chloride channels, restoring their function to that of wildtype CFTR .
Several classes of correctors of defective deltaF508-CFTR cellular
misprocessing were discovered, including bisaminomethylbithiazoles,
that improve mutant CFTR folding and facilitate its stability and targeting
to the cell plasma membrane, restoring cAMP-stimulated chloride
permeability . Small-molecule modulators of CFTR function are in development
for the treatment of cystic fibrosis, secretory diarrhea and
polycystic kidney disease .
Pedemonte, N ., N .D . Sonawane, A . Taddei, J . Hu, O . Zegarra-Moran,
Y .F . Suen, L .I . Robins, C .W . Dicus, D . Willenbring, M .H . Nantz, M .J .
Kurth, L .J . Galietta and A .S . Verkman (2005) . Phenylglycine and sulfonamide
correctors of defective deltaF508- and G551D-CFTR chloride
channel gating . Mol . Pharmacol . 67:1797-1807 .
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
deltaF508-CFTR cellular processing identified by high-throughput
screening . J . Clin . Invest . 115:2564-2571 .
s03.1
is the era of genetic counseling over?
S. Kessler;
Department of Molecular and Cell Biology, University of California at Berkeley,
Berkeley, CA.
s03.2
medical genetic services in developing nations
A. Christianson;
Division of Human Genetics, National Health Laboratory Services & University
of the Witwatersrand, Johannesburg, South Africa.
An expert advisory group of the WHO recognized in the early 1980’s
that health (epidemiological) transition would require developing countries,
within the foreseeable future to develop medical genetic services .
To that end the expert advisory group developed an approach cogent
for developing nations that focused on community based medical genetic
services integrated into primary health care and closely linked to
secondary and tertiary health care services .
In the latter half of the last century these approaches were refined, to
an extent based on services that were being established in a few developing
countries . This decade several middle-income nations have
recognized the need to develop medical genetic services, initially for
the care and prevention of birth defects . Following the approach proposed
by the WHO these nations are developing medical genetic services,
some with assistance from the March of Dimes and the World
Alliance of Organizations for Prevention and Treatment of Genetic and
Congenital Conditions (WAO) . Numerous barriers to the establishment
of these services still exist, but are being overcome .
s03.3
Personalized medicine and Genetic services: the Us model
M. Aspinall;
Genzyme Corporation, Westborough, MA, United States.
A revolution is underway in the life sciences and health care industry
. Fueled by the mapping of the human genome and a deepening
understanding of human genetic variation and ongoing advances in
diagnostics are expanding our understanding of the molecular basis
of disease . Health care delivery is beginning to shift from trial-anderror
medicine to patient-centric medicine . Patient care is becoming
focused on highly targeted and individualized diagnostic and treatment
regiments . The use of genetic services is expanding in all areas . This
revolution is known as personalized medicine .
Personalized medicine is a movement away from defining diseases by
their symptoms and locations within the body, and toward understanding
them through their underlying genetic causes . With a successful
transition to this model, more specific disease diagnoses will occur,
resulting in a personalized treatment plan for individual patients . Costs
will be reduced through more accurate diagnosis, improved drug efficacy
with fewer adverse drug reactions as well as improved patient
drug compliance . This trend to personalized medicine and increased
use of genetic services is occurring today in the field of oncology and
will expand to all areas of medicine .
The field of genetics services - both testing and counseling - is essential
to the implementation of personalized medicine . Without these
services, physicians and other healthcare providers will not be able to
access the information necessary to make the most informed choices
for patients .
Personalized medicine, however, must overcome multiple challenges
if it is to fully adopted. There are significant challenges involving physician
and patient education and acceptance . An expanded understanding
of genetics and diagnostics and its impact on patient care will be
necessary for all healthcare providers . A health information infrastructure
must be able to accommodate the accumulation and analysis of
expanding patient and pharmacogenomic data .
In this talk, I will review the current status of personalized medicine in
the United States including examples of its current impact on patient
care . I will also describe the current United States diagnostic market
including the current distribution systems and infrastructure design .
s03.4
the clinical Use of Genetic and molecular Biomarkers: A Public
Health Perspective
R. Zimmern;
PHG Foundation Cambridge, Strangeways Research Laboratory, Cambridge,
United Kingdom.
Advances in genomic science have led to a much greater knowledge
of disease mechanisms and the development of novel technologies
such as genetic tests and molecular biomarkers . Unlike the well trodden
pathway that exists for pharmaceutical products, we do not have
within Europe (or anywhere across the developed world) an effective
framework for their clinical evaluation . The absence of mechanisms
for generating the necessary data, or of institutions that focus on their
analysis, and the lack of policy about the respective responsibilities or
the public and commercial sectors for their establishment and funding
are major concerns for the practice of medicine and for public health .
The lecture will argue that an approach to the introduction of tests into
clinical practice based on clinical judgement is longer sustainable . The
complexities of modern diagnostics will require a more formal and innovative
approach . Tests will require explicit evaluation to identify the
clinically valid and useful . Biomarkers that are predictive of complex
disease before its development, in contrast to diagnostic or prognostic
markers or to genetic tests for high penetrance single gene disorders,
pose a particular challenge . The low relative risks that these show,
and the fact that each individual biomarker will be neither necessary
nor sufficient for the development of disease suggests that a different
approach to their assessment will be needed .