Bezafibrate Trial in CPT2 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).