Carnitine Palmitoyl Transferase 2 Deficiency Clinical Trial
Official title:
Clinical Trial on the Effect of Bezafibrate in the Muscular Form of Carnitine Palmitoyltransferase 2 Deficiency
The purpose of this study is to determine whether bezafibrate is effective in the treatment of the muscular adult form of carnitine palmitoyltransferase 2 deficiency
Fatty acids are the main source of energy for non-glucodependent tissues during fasting and
prolonged exercise. Carnitine Palmitoyltransferase (CPT) 1 and 2 are a key-enzymes in the
regulation of mitochondrial FAO, by governing entry of long-chain fatty acids within the
mitochondrial matrix. CPT2 deficiency is among the most common inherited disorders of
mitochondrial fatty acid oxidation (FAO). The neonatal and infantile forms of CPT2 deficiency
are life-threatening diseases with a hepatocardiomuscular presentation. The adult form
presents as recurrent attacks of rhabdomyolysis, mostly triggered by prolonged exercise,
fasting, and infections, and is usually considered as a "mild" disease. However, patients
commonly suffers permanent muscle weakness, and/or frequent (weekly, and sometimes daily)
attacks of rhabdomyolysis, that occasionally result in severe episodes of acute renal
insufficiency, and rarely in sudden death.
Difference in the clinical severity of the distinct forms of CPT2 deficiency correlates in
some extent with in vitro data. Thus, when measured in fibroblasts or lymphocytes, the
residual CPT2 activity and the long-chain fatty acid oxidation (LCFAO) are usually less than
10% of control values in the neonatal and infantile forms, while they most often are over 20
% of controls in the adult form.
Clinical management of CPT2-deficient patients remains poor, and most often does not succeed
in significantly improving their clinical condition. Treatment mostly relies so far on
restriction in lipid intake and limitation of fasting and exercise. We decided a few years
ago to set up a project of pharmacological therapy for this disease, based upon in vitro
testing of pharmacological agents potentially able to increase the residual enzymatic
activity in CPT2-deficient cell lines. Some of the best "candidate" drugs were PPAR agonists,
used since over two decades as hypolipidemic drugs. PPAR alpha is a transcription factor
belonging to the superfamily of steroid-thyroid nuclear receptors, that has been shown to
regulate the constitutive expression of the CPT2 gene and protein in the adult mouse heart
and liver and to mediate up-regulation of the CPT2 gene in response to fibrates in mouse
liver. We recently shown that bezafibrate, a PPAR alpha agonist, was able to restore close to
the normal the apparent CPT2 activity and the LCFAO in both fibroblasts and cultured
myoblasts from several patients with the adult form of CPT2 deficiency. Therefore, the
purpose of the current application is to test in vivo the potentially beneficial effect of
bezafibrate therapy in a cohort of 12 patients with the adult form of this disease. All
patients are clinically managed by either of the 2 research groups involved in this project,
namely the Neurology department of l'hospital Pitié-Salpétrière and the Genetics department
of l'hospital Necker-Enfants Malades. Patients fulfilling inclusion criteria will first be
submitted to a 6-month period of clinical and biological survey, with a written registration
of each clinical symptoms, and measurement of CK activity once a month. The initial
examination will include i) muscular testing, ii) measurement of CPT2 activity , LCFAO, and
quantitation of CPT2 transcripts both in lymphocytes and in a fresh small sample of skeletal
muscle, and iii)assay of acylcarnitines, a compound accumulated upstream of the metabolic
block, in blood. Bezafibrate will thereafter be daily supplied as a 400 to 600 mg dose,
according to the renal function, for 6 months. Follow-up will focus on the muscular
symptomatology and on the hepatic, muscular, and renal tolerance of the treatment. At the end
of the clinical trial, each patient will be submitted to an examination similar to the
initial one, including a second muscle biopsy used for measurement of CPT2 activity , LCFAO,
and amount of CPT2 transcripts. It has to be emphasized that, for the first time, such a
therapy should impact directly the cause of the disease (the defective enzyme activity) and
not only its consequences (accumulation of cell lipid and defective energy production).
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| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Active, not recruiting |
NCT02635269 -
Fat and Sugar Metabolism During Exercise in Patients With Metabolic Myopathy
|
N/A |