Within this complete European consortium animal models as well as patient material are utilized, in order to uncover the pathogenic pathways in OPMD that are at the centre of the disease, eventually in order to design rational evidence based…
ID
Source
Brief title
Condition
- Muscle disorders
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Outcome measures of our part of the study are:
- Identification of deregulated pathways by OPMD onset by transcriptome
analysis on the biopsies from presymptomatic OPMD patients.
- Identification of deregulated pathways involved in disease progression.
- Identification of deregulated pathways involved in the specific distribution
of muscleweakness in OPMD.
- Correlation of histological and clinical data of Dutch OPMD patients
Secondary outcome
The clinical and demographical characteristics like age, sex, body weight,
length, age at onset, first complaint at onset, disease severity, co-morbidity
and blood parameters (CK, ASAT, ALAT and LDH)
Background summary
Oculopharyngeal mucular dystrophy (OPMD) an autosomal dominant, late onset
(>40yrs), muscular dystrophy which is clinically characterized by progressive
ptosis, dysphagia and limb-girdle muscle weakness. OPMD is a rare disease
(1:100000) with a worldwide distribution. In some ethnical groups the incidence
is higher like the French Canadians in Quebec and the Bukhara Jews in Israel.
OPMD is caused by a GCG-repeat expansion in the genes encoding the
poly(A)binding protein nuclear 1 (PABPN1). This GCG repeat encoding an alanine
tract expansion at the N-terminus of the protein. The mutant form of PABPN1
contains 12-17 alanines, while 10 alanines are present in the normal protein.
Intranuclear inclusions (INI*s) in muscle fibers are a pathological hallmark of
OPMD. Despite the fact that the genetic cause of OPMD is known, little is known
about the molecular mechanisms leading to INI*s and muscle dysfunction and the
reason why the mutation only affects specific muscle groups. Like other
proteinopathies, or diseases that are associated with the formation of
protein-aggregated in affected tissues, such as Huntington*s, there is no
pharmacological treatment for this disease. Recent data suggest that these
intranuclear inclusions contain mutant insoluble PABPN1 molecule (Calado et al.
2000) as well as ubiquitin (= a regulatory protein which tags broken proteins
to degrade them via the ubiquitine-proteasome system, UPS) and the subunits of
the proteasome (=large protein complex which degrades proteins). The current
view is to explain these results is that the polyalanine expansios in PABPN1
confer a toxic "gain-of-function" to the protein, and induce misfolding and
aggregation to PABPN1 inclusions, which are then targeted to the
ubiquitin-proteasome degradation pathway (Calado et al 2000). But recent data
suggest that the ubiquitin-proteasome system itself seems to be the predominant
deregulated pathway in OPMD patients (Anvar et al 2011). Anvar 2011 found that
exression of expPABPN1 leads to down-regulation of proteasome-encoding genes.
In turn, proteasome down-regulation during muscle aging triggers expPABPN1
accumulation and accumulation of exp PABPN1 leads to extensive proteasome
down-regulation. This feed forward model could justify the appearance of INI*s
in specific muscles and the late onset of the disease. Recent data suggest
that, in myotubes of OPMD mice, the ratio of soluble/insoluble expPABPN1 is
significantly lower compared with that of the non-mutated (wildtype) protein.
This suggests that the difference in soluble/insoluble ratio of expPABPN1 can
contribute to muscle weakness in OPMD (raz et al Am J Pathol. 2011 Aug 17.)
The primary function of PABPN1 is nuclear polyadenylation, an mRNA processing
reaction leading to the formation of the poly(A) tail at the end of mRNA's
(Wahle 1991). In agreement with this, decrease PABPN1 levels in vivo in
drosophila and mouse myoblasts leads to shortened mRNA poly(A)tails (Benoit et
al 2005, Apponi et al. 2010). Consistent with this function, several lines of
evidence suggest that the involvement of mRNA metabolism in OPMD pathogenesis.
Recent data have also implicated apoptosis in OPMD pathogenesis (Chartier et al
2006, Davies et al. 2008).
The aim of this European consortium is to decipher the molecular mechanisms
involved in OPMD pathogenesis in order to base innovative therapeutic
strategies based on. The strengths of this consortium are the utilization of
different animal-models (mouse and Drosophila), each having a specific
advantage, as well as patient biopsies, and the variety and complementarity of
techniques and approaches utilized in the different laboratories of the
network.
Within this network a genetically tractable OPMD model has been generated,
using Drosophila- PABPN1 with a polyalanine extansion of different lengths.
Studies with this model have shown that although the polyalanine expansion is
required for the disease, the context of the disease is also essential. A
mouse model has been generated by expressing alanine-expanded PABPN1
specifically in skeletal muscle. Recent detailed phenotypic characterization of
this model mouse model in combination with transcriptome studies by members
if this consortium revealed progressive deregulation of the muscle atrophy
network with progressive muscle atrophy restricted to fast glycolytic fibres
(Trollet et al 2010). Biopsies from OPMD patients are also available in this
consortium. New biopsies will have to be collected. This will allow us to study
human muscle cells from affected as well as unaffected muscles in different
stages of the disease.
Finally, therapeutic tools and strategies have been developed previously, by
participants in this consortium. An antibody against PABPN1 has been identified
(Verheesen et al. 2006), which, when expressed intracellular in Drosophila
muscles, completely prevents OPMD symptoms, thus revealing its high
therapeutic potential (Chartier et al 2009).
Significant understanding of pathological mechanisms and consequent
evidence-based therapeutic approaches in rare diseases are severely hampered by
the difficulty in generating sufficiently large patient data sets and limited
availability of relevant bio-resources. In order to overcome this, our eOPMD
network combines clinical and basic research with the focus to understand the
pathophysiology of this rare muscular dystrophy and to design new therapeutic
approaches. Central to our research is the hypothesis that important pathogenic
pathways in OPMD are shared between diseased tissue and different cellular and
animal model systems.
The teams involved in present network are as follows, each of them having their
unique expertise:
Partner 1: Dr. Martine Simonelig . Institut de genetique Humaine UPR 1142 CNRS.
France.
Partner 2: Dr. Vered Raz. Leiden University medical Centre- Human genetics.
Partner 3: Dr. Gillian Butler-Browne. Institut de myologie UMRS 974. France.
Partner 4: Prof. George Dickson. Royal Holloway- University of London. UK.
Partner 5. Prof. Dr. Baziel van Engelen. Radboud university Nijmegen Medical
centre. Dept. Neurology.
Our contribution to this study will be:
- Repeating musclebiopsies from the same Dutch OPMD patients who were biopsied
previously, in 2003 (protocolnumber d.d. 12-06-2002, CMO-nr: 2002/108).
- Muscle biopsies will also be taken from all newly diagnosed patients, known
in our centre.
- Muscle biopsies will also be taken from the adult offspring of the newly
diagnosed OPMD patients.
All biopsies will be taken from a clinically often affected muscle (quadriceps)
as well as a muscle which is often clinically unaffected (tibialis anterior).
This material will be subjected to transcriptome analysis, in order to
- Identify pathways involved in disease progression. By subjecting the first
(2003) and second (2011) quadriceps biopsy to transcriptome analysis, we will
investigate pathways involved in the disease progressiveness with reduced
inter-individual-variation noise.
- Identify pathways involved in the specific distribution of muscleweakness in
OPMD. By subjecting the clinically affected (quadriceps) muscle and the
clinically unaffected muscle (tibialis anterior) to comparative transcriptome
analysis, we will identify the molecular basis behind OPMD muscle group
specificity, with reduced inter-individual-variation noise.
- Identify deregulated pathways involved in disease onset. By subjecting the
muscle biopsies from the presymptomatic OPMD patients (that means the adult
offspring of an OPMD patient that carries the mutation but is not clinically
affected, yet) to transcriptome analysis and comparing them to the biopsies
from OPMD patients and comparing the quadriceps muscle to the tibialis anterior
muscle within the same presymptomatic individual, we will identify deregulated
pathways involved in disease onset. See flowchart 2 on p. 22 of the protocol.
Furthermore we will take questionnaires from all the symptomatic OPMD patients,
concerning onset, course, current symptoms and impact of the disease. We will
subject all the participants to a standardized neurological exam including a
muscle power measurement using the handheld dynamometer and a venipuncture in
order to perform DNA analysis (if not performd before) and laboratory values
(CK, ASAT, ALAT and LDH) in order to correlate clinical, histological and
genetic aspects in the Dutch OPMD population, which is never described to this
extend.
Within our study we contribute to OPMD research twofold:
By contributing to this multicentre study we help in clearing up
pathophysiology of OPMD. On the other hand we describe the Dutch OPMD
population.
These results, combined with the results from the animal models within this
eOPMD project, will be used as a basis for future clinical trials with gene-
and pharmacological therapies.
Study objective
Within this complete European consortium animal models as well as patient
material are utilized, in order to uncover the pathogenic pathways in OPMD that
are at the centre of the disease, eventually in order to design rational
evidence based therapeutic strategies for this largely neglected muscular
dystrophy.
We utilize different animal models (each having their advantage) as well as
patient material and a variety of genetic and molecular techniques and
approaches utilized in the different laboratories in our network. This will
allow us to:
A. Identify cellular pathways underlying OPMD pathology.
B. Validate information obtained in animal models (e.g. through genetic
approaches) up to patient material.
C. rapidly test therapeutic approaches and identify those with the highest
therapeutic potential.
The research is based on the hypothesis that important pathogenic pathways in
OPMD are shared between diseased tissue and different cellular and animal model
systems. Combining the advantages of cross-species transcriptome analysis, fast
and efficient genetic and suppressor screens in Drosophila, function studies in
mice and validation in human cells and tissues, we aim to uncover those
pathogenic pathways in OPMD that are at the centre of the disease with the
objective to design rational evidence-Based therapeutic strategies for this
largely neglected muscular dystrophy.
The objectives of this complete research are divided among the 5 partners:
Aim1: (partner 1 and 3) Identification of the molecular pathways involved in
OPMD through genetic screens using the drosophila model.
Aim2: (responsible partner 2, participant partners 1-5) understanding the
mechanisms underlying the pathophysiology of OPMD by
a.)Identification of OPMD deregulated pathways by trans-model transcriptome
analysis.
b.) Validation of OPMD deregulated pathways in the mouse model and on human
biopsies.
c.) Functional validation of the biological pathways deregulated in OPMD using
the drosophila model
d.) Identification of OPMD deregulated pathways by transcriptome and proteome
analysis
e.) Correlating the clinical and the histological pathways in OPMD patients.
Aim3: (responsible partner 3, participant partners 3, 4) Development of gene
strategies for OPMD.
Aim4: (Responsible partner 4, participant partners 1, 4) Pharmacological
approach to treat OPMD.
The aims specific for our centre will be:
A. contributing to this multicentre research by taking two muscle biopsies from
Dutch OPMD patients and their adult offspring. With the sub-objectives:
I. Identify pathways involved in disease progression. By subjecting the first
(2003) and second (2011) quadriceps biopsy to transcriptome analysis.
II. Identify pathways involved in the specific distribution of muscleweakness
in OPMD. By subjecting the clinically affected (quadriceps) muscle and the
clinically unaffected muscle (tibialis anterior) to comparative transcriptome
analysis.
III. Identify deregulated pathways involved in disease onset. By subjecting
the muscle biopsies from the presymptomatic OPMD patients (that means the adult
offspring of an OPMD patient that carries the mutation but is not clinically
affected, yet) to transcriptome analysis and comparing them to the biopsies
from OPMD patients and comparing the quadriceps muscle to the tibialis anterior
muscle within the same presymptomatic individual.
B. Correlating clinical, histological and genetic characteristics of Dutch
OPMD patients
Study design
- We have a database with all the OPMD patients known in our clinic since
2003. We will send all these patients information concerning this study and ask
them whether they want to participate.
- From the patients on this list, we know whom participated in the preceding
study (Protocolnr: d.d. 12-06-2002, CMO-nr: 2002/108). We will only contact the
adult offspring from the OPMD patients who did not participate in the preceding
study, in order to send them information about this study and ask whether they
want to participate
- As soon as the informed consents are returned, we will send the
questionnaires to the symptomatic OPMD patients and we will make an appointment
for the examinations with all the participants.
- On the planned day we will perform on all the participants: a short medical
history and
- a neurological exam including a muscle power measurement, using the hand held
dynamometer.
- a venipuncture will be performed to screen DNA for the OPMD specific mutation
(if not performed before) and to assess for parameters of muscle injury (CK,
ASAT, ALAT, LDH)
- a needle muscle biopsy of 2 muscles (m. quadriceps and m. tibialis anterior)
will be performed.
- transcriptome analyses on de cells from the muscle biopsies will be performed
by partner 2, LUMC
- histological analysis will be performed in our centre.
- We will correlate clinical, histological and genetic data of the complete
Dutch OPMD population.
Study burden and risks
For this project the participants have to travel once to the Radboud University
medical Centre Nijmegen. The examinations are planned on 1 part of the day. The
only burden for the participants is the time they have to make. The biopsy and
the blood collection are no additional risks for the patients.
47-83 boulevard de l'Hôpital
75651 Paris Cedex 13,
FR
47-83 boulevard de l'Hôpital
75651 Paris Cedex 13,
FR
Listed location countries
Age
Inclusion criteria
- Age between 18-80 years
- Phenotype of autosomal OPMD. This phenotype inlcudes a positive family history with involvement of two or more generations.
-The presence of ptosis (defined as either vertical separation of at least one palpebral fissure that measures less than 8 mm at rest) OR previous corrective surgery for ptosis
-The presence of dysphagia, defined as swallowing time greater than seven seconds when drinking 80 mL of ice-cold water
- Or confirmd OPMD by a 12-17 alanin trinucleotide repeat of the PABPN1 gene.
- Or adult offspring of a newly diagnosed OPMD patient (and thus did not participate in the 2003 study)
Exclusion criteria
- serious external ophtalmoplegia before the age of 60
- presence of myotonia
- comorbidity affecting muscle dysfunction
- abnormal bleeding
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
CCMO | NL38086.091.11 |