Main objective: - To investigate pyruvate kinase thermal stability in haemoglobinopathies.Secondary objectives: - To investigate the possibility of stimulation of PK activity and thermal stability by use of allosteric activators- To investigate…
ID
Source
Brief title
Condition
- Haemoglobinopathies
- Blood and lymphatic system disorders congenital
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- To investigate pyruvate kinase thermal stability in haemoglobinopathies:
Parameters of interest are PK activity and thermal stability. Results obtained
from patient cells will be compared with those from healthy controls, and
between the different disease groups.
Secondary outcome
- Stimulation of PK in haemoglobinopathies by use of allosteric activators:
A comparison will be made between treated and untreated samples. Parameters of
interest are glycolytic and pentose phosphate pathway intermediates, and
biomarkers of oxidative stress.
- Oxidative stress as a cause of decreased PK thermal stability in
haemoglobinopathies:
Conditions of severe oxidative stress will be mimicked by incubating red blood
cells of both participants and healthy controls with oxidative agents with or
without reducing compounds The endpoint is the difference in levels of
glycolytic and pentose phosphate pathway intermediates and biomarkers of
oxidative stress between oxidized and reduced samples.
- The role of PK thermal stability related to clinical symptoms and clinical
disease severity:
Parameters of interest are incidence and prevalence of disease related organ
damage, transfusion burden, historical lab parameters and medication history
Background summary
Haemoglobinopathies encompass all genetic diseases of haemoglobin. Patients
with haemoglobinopathies suffer from anaemia because of premature red blood
cell destruction. The pathophysiology behind this is multifactorial and
complex. However, increased oxidative stress is a common pathophysiologic
feature that is shared by all haemoglobinopathies.
Pilot studies in our laboratory have shown that pyruvate kinase shows decreased
stability in haemoglobinopathies. Since pyruvate kinase is essential for red
blood cell energy supply and anti-oxidative defence we postulate that this
instability could compromise red cell metabolism, and thereby, cellular
survival. Also, by retrograde accumulation, loss of PK activity could lead to
an increase in 2,3-DPG, which in turn is an important regulator of oxygen
affinity of haemoglobin. Lowering 2,3-DPG levels is currently used as a
therapeutic target in several clinical trials in sickle cell disease.
Currently, in our laboratory and clinic, pyruvate kinase-activators are tested
that have been designed to treat the rare hereditary disease pyruvate kinase
deficiency. Recently, the use of these allosteric activators has been extended
to the field of thalassaemia, a common form of haemoglobinopathy. A study in a
mouse model of thalassaemia showed successful stimulation of pyruvate kinase
function resulting in increased haemoglobin levels in vivo. We therefore aim to
further explore the role of decreased stability of PK in several forms of
haemoglobinopathies in humans, and study the effect of restoring this
instability by the use of allosteric activators ex vivo.
Study objective
Main objective:
- To investigate pyruvate kinase thermal stability in haemoglobinopathies.
Secondary objectives:
- To investigate the possibility of stimulation of PK activity and thermal
stability by use of allosteric activators
- To investigate oxidative stress as a cause of decreased pyruvate kinase
thermal stability in haemoglobinopathies
- To investigate the role of PK thermal stability related to clinical symptoms
and disease severity
Study design
Case Control study
Study burden and risks
Patients and healthy controls are asked for a single blood donation of 57 ml
via venepuncture. Physical discomfort may include bruising. Also patients are
asked permission for medical chart review.
88 Sidney Street 88
Cambridge MA 02139
US
88 Sidney Street 88
Cambridge MA 02139
US
Listed location countries
Age
Inclusion criteria
Group 1: 20 Homozygous (HbSS) sickle cell patients or patients with compound
heterozygosity for sickle cell disease and β-(0)-thalassemia. 10 patients with
compound heterozygosity for sickle cell disease and hemoglobin C disease.,
Group 2: 20 β-thalassemia intermedia or major patients, Group 3: 5 unstable Hb
patients, Group 4: 15 other hereditary anemia patients, In order to be eligible
to participate in this study, a subject must meet all of the following criteria:
- Adult patients (18 years or older) with a diagnosis as listed above
- Participant is willing and able to give informed consent
Exclusion criteria
Exclusion criteria:
- Inability to give informed consent.
- Need for regular red blood cell transfusions (more than 12 transfusions a
year)
- Recent transfusion, defined as within 1 months prior to enrolment).
The last two criteria do not lead to exclusion for patients with Unstable Hb,
because of the extreme rarity of the diagnosis.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| CCMO | NL59957.041.17 |