Oculo-Pharyngeal Muscular Dystrophy (OPMD), is characterised by the selective affection of the superior sphincter muscles of the oesophagus (SSO) and the pharyngeal.muscles resulting in dysphagia. The most common treatment for the dysphagia induced by this disease is a myotomy.. However, although this will relax the constriction and improve swallowing it will not prevent the progressive degradation of the pharyngal muscles. This progressive loss of contractility will eventually result in false routes and severe difficulty in swallowing, increased risk of pulmonary infection and severe weight loss which are the most common causes of mortality in these patients.

 

The protocol which we are proposing is a pilot study in which autologous myoblasts isolated from unaffected limb muscles will be grafted into the pharyngeal constrictor muscles of patients diagnosed as suffereing from OPMD. Our aim is to improve both swallowing and the contractile deficit generated by the dystrophic pharygeal constrictor muslces. A myotomy of the SSO willl be carried out at the same time as the myoblast transplantation, since we have already validated the improvement resulting from this surgery even though we know that this will provide only a partial and transitory improvement.

 

This is a multicentric trial with a direct benefit for the patient in which 10 patients will receive an autologous transplantation of myoblasts. Due to the possibility that a certain number of patients may withdraw from the study we have decided to include initially a maximum of 15 patients. The PHRC for this clinical trial was accepted in 2002 and the official promotor is the AP-HP. The patients will be selected by the different promotors but will be followed in  the "Service d'ORL de l'Hôpital Tenon". The proliferative capacity of the myoblasts isolated from the muscle biopsies will be carried out by Vincent Mouly and Kamel Mamchaoui in the UMR 7000 CNRS directed by Dr Butler-Browne and the cells will be amplified prior to grafting in the "Laboratoire de Th‚rapie Cellulaire" of Dr Marolleau; The clinical trial will be controled by a specifically selected comittee of five.

 

In the first step of this study patients will be selected for inclusion in the trial according to the following criteria : 1 : men or women aged between 18 and 75 years ; 2 :genetic confirmation and characterisation of  OPMD 3: SSO dysfunction confirmed by the stasis of saliva or food above the sphincter visualised by fibroscopy and a defect in the opening of the SSO also confirmed by radiocinema; the SSO defect may be associated with a reduction in pharyngeal propulsion as revealed by fibroscopy and radiocinema of swallowing 4: official signed consent of the patients to participate in this clinical trial.

 

The next step will be the selection of the unaffected muscle to be used for the production of the autologous myoblasts to be used for transplantation. Muscles will be selected for engraftement on the basis of the proliferative capacity of the cultures made from biopsies (0.5-1gm) obtained following local anesthesia of either the quadriceps or the sterno-cleido-mastoidien muscles.. The muscle which is able to produce the largest number of myoblasts will be biopsied a second time using the same conditions. Two grams of muscle will be removed and the myoblasts will be isolated and cultured until there are about 100 million myoblasts at which point the cells can be injected into the pharyngeal muscles of the patient. If there is no difference between the two different muscle biopsies then we will biopsy preferentially the sterno-cleido-mastoidien muscle since it is situated directly in the trajectory that will be used when grafting the myoblasts. The operation by lateral cervicotomy will be carried out under general anesthsia, in order to expose the SSO and the pharyngeal muscles. The graft will be carried out by injecting the myoblasts into about 20 different sites in the pharyngeal constrictor muscles above the site of the associated myotomy of the SSO. The next step will involve a two year evaluation of the trial. For each patient a descriptive analysis will be carried out based on the comparison of the different  results. The pricipal evalution of the efficiency of the graft will be based on the functional quality of the pharyngeal propulsion as determined by fibroscopy and radiocinema of swallowing. A secondary evaluation will be based on the global swallowing properties which will be evaluated by a quantitative test, by a questionnaire and by an evaluation of  the tolerance. This evalution will include a rigid tube pharyngeal endoscopy which will be carried out under general anesthsia 6 to 12 months after the graft in order to confirm the absence of muscle tumors, a clinical examination at each visit consisting of the examination of the pharynx and a cervical palpation in order to determine the volume of the muscle and to survey the site of myoblast implantation. In addition, a global neuromuscular examination will be carried out on an annual basis to follow the general evolution of the myopathy. The fibroscopy to determine the swallowing function, the global quantitative tesy of swallowing and the questionnaire will be carried out at 2, 6 and 24 months after the graft . A radiocinematic examination will be carried out at 2 months then at 1 and 2 years after the graft.

 

The principal benefits to the patients which could be envisioned by this procedure is a delay in the deterioration of the pharygeal muscles associated with this disease and consequently an improvement in the difficulties in swallowing usually associated with this disease. The potential risk associated with this type of operation are an inflamatory reaction, the appearance of a tumor or the lack of improvement of the syptoms associated with the disease.
A parallel preclinical study has been carried out in the dog in order to evaluate the tolerance and feasability of the procedure for autografting myoblasts in the pharygeal muscles.