Personalized Medicine of Dementia

100 Pages·2010·7.48 MB·English

DICIEMBRE 2009 | Nº 4 | P.V.P 5,00€
FARMACOGENÉTICA PERSONALIZED EFFECTS OF FR-91
DE LOS AINEs MEDICINE OF ON HUMAN TUMOR
Personalizar el DEMENTIA CELL LINES
Tratamiento Pharmacogenomics of
Alzheimer´s Disease
www.gen-t.es
Pídanos cita: Más información:
[phone] www.euroespes.com
Centro Médico EuroEspes:
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EDITORIAL
Ramón Cacabelos
A modo de Presentación
por Ciprián Rivas
Gen-T Número 4
Diciembre 2009
Ciencia y divulgación
Editorial
EuroEspEs publishing
Optimize sus defensas naturales
A modo de Presentación
por Ciprián Rivas
DefenVid ® (E-JUR-94013 ®)
es el primer nutracéutico biomarino
con estructura lipoproteica natural
que presenta propiedades de
inmunopotenciación y regulación
metabólica e inmunoglobulínica
19 de Diciembre de 2009, Bergondo, La Coruña
8:30 RECEPCIÓN 14:00 COMIDA
9:00 Acto inaugural 16:00 Sesión Plenaria-III
Farmacogenética de los AINEs
9:30 Sesión Plenaria-I Prof. Dr. J.A. García-Agúndez
Farmacogenómica de los trastornos metabólicos Departamento de Farmacología y Psiquiatría
Prof. Dr. Andreas Pfützner Facultad de Medicina, Universidad de Extremadura,
PharmGenomics, Mainz, Alemania Badajoz
10:15 Estrategias terapéuticas en la enfermedad de 16:45 Modelos transgénicos en enfermedades
Alzheimer neurodegenerativas
Dr. X. Antón Álvarez Dr. Iván Carrera
Departamento de Farmacología Clínica y Experimental Departamento de Neurociencias
Centro de Investigación Biomédica EuroEspes, Coruña EuroEspes Biotecnología (Ebiotec), Coruña
10:45 Genómica clínica de los trastornos del movimiento 17:15 Neurodegeneración y cáncer
Dra. Lucía Fernández-Novoa Dr. Salvador Harguindey
Departamento de Genómica Médica Instituto de Biología Clínica y Metabolismo
EuroEspes Biotecnología (Ebiotec), Coruña Vitoria, Álava
11:15 DESCANSO 17:45 DESCANSO
11:30 Sesión Plenaria-II 18:00 Aplicaciones actuales de la farmacogenética en
Medicina personalizada en el abordaje clínico de la terapias del cáncer
demencia: Farmacogenómica de la enfermedad de Dr. Stefan Prause
Alzheimer PharmGenomics GmbH
Prof. Dr. Ramón Cacabelos Mainz, Alemania
Departamento de Neurociencias Clínicas
Centro de Investigación Biomédica EuroEspes, Coruña 18:30 Fibronectina en la enfermedad de Alzheimer
Prof. Dr. Jerzy Leszek
12:15 Farmacogenética de los tratamientos Medical University of Wroclaw
anticoagulantes Wroclaw, Polonia
Dra. Ruth Llovo
Departamento de Farmacogenética 19:00 Acto de clausura
EuroEspes Biotecnología (Ebiotec), Coruña Presidido por D. Augusto Silva
Director General Terapias Avanzadas y Trasplantes
12:45 Genómica de la patología cerebrovascular Ministerio de Sanidad y Consumo, Madrid
Dr. Juan Carlos Carril
Departamento de Genómica e Identifcación Humana
EuroEspes Biotecnología (Ebiotec), Coruña
FUNDACIÓN
SEDE: Centro de Investigación Biomédica EuroEspes, Bergondo, Coruña, España | ORGANIZA: Fundación EuroEspes
EUROESPES
SUMARIO
Opinión
03 Editorial
04 A modo de presentación
Ciencia
08 Pharmacogenomics of
Personalized medicine of dementia Metabolic Disease
Pharmacogenomics of Alzheimer´s disease 18-48
18 Personalized medicine of
dementia: Pharmacogenomics
of Alzheimer´s disease
50 Effects of FR-91on human
tumor cell lines
62 Farmacogenómica de los
AINEs
70 Genómica de la patología
cerebrovascular
Farmacogenómica de los AINEs
62-68
Sociedad
86 Cooperación multisectorial
para impulsar el desarrollo de
Galicia
88 III conferencia anual
EuroEspes
Noticias
Effects of FR-91 on human
tumor cell lines 50-60 94 Noticias EuroEspes
Suscripción
98 Boletín de suscripción
Genómica de la patología
cerebrovascular 70-84
diciembre 2009 7
Pharmacogenomics
of Metabolic Disease
Andreas Pfützner1,2, Stefan Prause2, Moritz Eidens2, Alexander Weise1, Thomas Forst1
1. IKFE - Institute for Clinical Research and Development, Parcusstr. 8, D-55116 Mainz, Germany
2. PharmGenomics GmbH, Parcusstr. 8, D-55116 Mainz, Germany
8
Sumary
he prevalence of metabolic diseases, such as and will help to avoid the otherwise unavoidable
atherosclerosis, diabetes mellitus and cardio- progression of metabolic syndrome, cardiomet-
metabolic syndrome, has reached pandemic di- abolic syndrome or type 2 diabetes mellitus to
mensions. The increasing incidence in emerg- fnally end in macrovascular death.
T ing countries, which is linked to an improved
access to processed food, will make these dis-
eases the major burden for the affected health
care systems. Orchestrated by a complex interac- Introduction
tion of the joint underlying pathophysiological
deteriorations (insulin resistance, ß-cell dysfunc- Type 2 diabetes mellitus is one of the most fre-
tion, visceral adipogenesis, and chronic systemic quent diseases with a worldwide prevalence of
infammation), the disease presents with a vari- 4-5 % and a 10 % annual incidence rate. The ma-
ety of clinical phenotypes, characterized by dif- jor pathophysiological drivers are a hereditary
ferent compositions and severities of the most or metabolic insulin resistance in combination
common symptoms: hypertension, dyslipidemia, with the inability of the pancreas to augment in-
hyperglycemia and atherosclerosis. The disease sulin secretion to the required amoun1.t About
diagnosis is usually defned by the major symp- 40 % of the US population are overweight and
toms and (e.g.) many patients with normoglyce- develop insulin resistance. In the majority of
mic vascular insulin resistance die from a mac- these cases, the pancreas is able to counterbal-
rovascular event without ever being treated with ance the increasing insulin need by an appro-
a drug affecting insulin resistance. These drugs priately increased secretion. However, in a sig-
are normally only prescribed in case of overt nifcant minority of about a third of these cases,
diabetes with hyperglycemia. On the contrary, a concomitant ß-cell dysfunction leads to the
even well controlled patients with diabetes die development of a metabolic syndrome and to
from macrovascular events because the interna- diabetes mellitus2. Insulin resistance, however, is
tionally accepted therapy guidelines target high also associated with an increased cardiovascular
blood glucose levels and HbA1c only and disre- risk and the majority of the patients fnally die
gard the macrovascular risk induced by insulin from myocardial infarction or other macrovas-
resistance and the infammatory activity of the cular complication3s, 4.
visceral lipid tissue.
The disease is commonly regarded as chronic
All these fndings underline the immediate ne- progressive and general treatment guidelines are
cessity to develop diagnostic approaches for in- available to guide physicians how to best reach
dividualized assessment of the diverse contribu- normoglycemia, which is commonly defned via
tions of the underlying disease components to a hemoglobin A1c value in the target range of <
the patient risk profle. Such approaches would 6.5 % (Europe) or < 7.0 % (USA5), 6. However,
help to improve the major challenges in this in- recent outcome studies have demonstrated that
dication: identifying patients at risk of disease HbA1c is only a very moderate surrogate marker
development, monitoring the effcacy of pre- with limited or almost no prognostic value for
ventive measures, identifying the most optimal the prediction of cardiovascular outcome.
therapeutic approaches and monitoring their
effectiveness in patients with overt disease, and
identifying patients at a very high risk for macro-
vascular events justifying intense and expensive
treatment interventions.
Appropriate diagnostic options can be identi-
fed at all levels of cellular activity starting with
DNA markers for risk identifcation based on de-
termination of candidate gene mutations (usu-
ally linked to ß-cell function or atherosclerosis),
assessment of increased mRNA expression (e.g.
as a measure of macrophage activation), and de-
termination of plasma protein levels of biomark-
ers specifcally associated with the related dis-or
ders. Modern laboratory platforms, such as the
MutaChip technology, allow for economic and
specifc determination of DNA, mRNA, and pro-
tein biomarker panels to increase the effcacy of
individually selected therapeutic interventions,
diciembre 2009 9
Ciencia
Pharmacogenomics of Metabolic Disease
genetic predisposition or other environmental
factors including excess food uptake and devel-
opment of obesity. Increased insulin resistance
anti-insuline hormones demands for increased insulin secretion, which
adiponectin is normally provided by the ß-cells in a compen-
satory manner to lower blood glucose levels into
the normal range. However, insulin is the only
insulin resistance physiological hormone known to induce growth
of lipid tissue, and an increase in body weight
will most likely occur in the presence of suff-
cient food supply. It has recently been shown
insulin
that growth of visceral adipose tissue results in
requirement
differentiation of mesenchymal stem cells to pre-
adipocytes, which fnally become mature lipid
cells. The pre-adipocyte, however, is the source
of a substantial number of different cytokines
ß-Cell adipogenesis
and hormones (referred to as “adipokines”)
dysfuntion
known to support insulin resistance and thus a
circle is closed leading to constantly increasing
insulin resistance and obesity (Fig. 1)14.
As long as the ß-cells are not compromised by
a ß-cell dysfunction, the situation may be meta-
insulin
bolically under control and can be reversed by
proinsulin
reduction of food intake and increased physical
exercise. However, in patients developing type
2 diabetes, ß-cell dysfunction will occur and will
further accelerate the disease progression. Dys-
function of the ß-cell in type 2 diabetes is com-
Fig. 1 5 prised of three components: secretion timing
The pathophysiological link between insulin resistance, ß-cell dysfunction and visceral disorder, quantitative disorder and qualitative
adipogenesis. disorder. An indicator for the secretion timing
disorder in early stages of type 2 diabetes is the
loss of frst phase insulin response, an important
In these trials, achievement and maintenance of inhibitory signal for hepatic glucose release15. In
the target HbA1c range for several years had no later stages, loss of pulsatile insulin release can
pronounced infuence on the incidence and out- also be observed as additional failure in secre-
come of cardiovascular events7, 8. While elevated tion timing16. The quantitative disorder starts
blood glucose is certainly a contributor to the when the ß-cell increases the volume of insulin
increased cardiovascular risk, even normaliza- release based on the increased external demand.
tion of HbA1c leaves the patient with substantial In later stages, increasing exhaustion of the pro-
further event risk9. It has to be concluded that duction capacity may result in complete loss of
current treatment guidelines address the under- insulin secretion17. An increased quantitative
lying pathophysiology only in a suboptimal way secretion of proinsulin, and - in parallel - also
and that new and more individualized treatment of other pro-hormones, like pro-islet amyloid
targets may be required to effectively improve polypeptide (which is processed by the same
the vascular prognosis of the affected patients. conversion enzymes as proinsulin18) can fnally
A closer investigation of the pathophysiology of- lead to a deterioration of the secretion product
fers surprising insights into this complex disease composition.
and offers attractive ways for identifcation of
suitable biomarkers for more effective and indi- When new assays for assessment of unprocessed
vidualized interventions. intact proinsulin became available, they helped
to understand previous fndings regarding el-
evated fasting proinsulin levels in the plasma of
non-diabetic patients19. In the natural develop-
Pathophysiology of the ment of type 2 diabetes, proinsulin may only be
cardiometabolic syndrome elevated in the case of a signifcant insulin re-
sistance, and we were thus able to demonstrate
The close relation between insulin resistance that elevated fasting morning intact proinsulin
and ß-cell dysfunction has long been established is indeed a highly specifc indicator for insulin
and confrmed in large epidemiological stud- resistance20. Proinsulin is able to lower glucose
ies10-13. Insulin resistance may occur based on levels but shows only 10-20 % of the effcacy of
10