Treatment of Dysphagia in Oculopharyngeal Muscular Dystrophy by Autologous Transplantation of Myoblasts
Condition: Muscular Dystrophy, Oculopharyngeal
MeSH terms: Muscular Dystrophies; Muscular Dystrophy, Oculopharyngeal; Deglutition Disorders
Study type: Interventional
Phase: Phase 2

Summary: 
      The OCULO-Pharyngeal Muscular Dystrophy (OPMD) is a late onset hereditary muscle disease
      which is characterised by the selective affection of the pharyngeal muscles resulting in
      swallowing disorders, and by a ptosis from the dysfunction of the levator palpebral superiors
      muscles. Swallowing disorders are determinant in the prognosis of the disease, and
      potentially life-threatening deglutition, due to aspiration and denutrition. Degenerative
      dystrophy of the pharyngeal muscles causes difficulties to prepulse the food bolus in the
      pharynx, and the decreased relaxation of the cricopharyngeal muscle induced by the disease
      leads to blockage of food in the upper esophageal sphincter. The most common treatment for
      the dysphagia in OPMD is a myotomy of the upper esophageal sphincter muscles. However,
      although this will relax the constriction of the upper esophageal sphincter muscles and
      improve transitory the swallowing, it will not prevent the progressive degradation of the
      pharyngeal muscles. This progressive loss of contractility will eventually result in
      aspiration and severe difficulty in swallowing, increasing risk of aspiration pneumonia and
      severe weight loss which are the most common causes of mortality in OPMD patients.

      The protocol which we are proposing is a graft of autologous cell muscles (myoblasts)
      isolated from unaffected limb muscles into the pharyngeal muscles of patients diagnosed as
      suffering from OPMD. Our aim is to improve both swallowing and the contractile deficit
      generated by the dystrophic pharyngeal muscles. A myotomy of the upper esophageal sphincter
      will be carried out at the same time as the myoblast transplantation, since we have already
      validated the improvement resulting from this surgery. Advantages of this new therapy in OPMD
      is the autograft, without risks of rejection, and the graft of myoblasts into the dystrophic
      pharyngeal muscles, above the myotomy of the upper esophageal sphincter muscles.

      This model of cellular therapy has been studied through a preclinical study performed in
      dogs, allowing to valid the procedure and its safety, as well as to study the survival
      myoblasts grafted in the pharyngeal muscles.

      This protocol is proposed for OPMD patients; it is firstly a safety study of both autograft
      and surgical procedure. In addition, the autograft may improve the swallowing disorders and
      life-threatening complications induced by aspiration and weight loss, resulting in a
      potential individual benefit.
    

Detailed description: 
      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 pharyngeal 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.

      Concept:

      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 suffering from OPMD. Our aim is to improve both swallowing and the
      contractile deficit generated by the dystrophic pharyngeal constrictor muscles. A myotomy of
      the SSO will 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.

      Type of trial: 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 of TENON Hospital '. The proliferative capacity of the
      myoblasts isolated from the muscle biopsies will be carried out by Vincent MOULY and KAMEL
      MANCHAOUI in the UMR 7000 CNRS directed by Dr Butler-Browne and the cells will be amplified
      prior to grafting in the Cellular laboratory therapy of Dr MAROLLEAU; The clinical trial will
      be controlled by a specifically selected committee of five.

      Description of the trial 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 videofluoroscopy of swallowing; the SSO
      defect may be associated with a reduction in pharyngeal propulsion as revealed by fibroscopy
      and videofluoroscopy 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
      engraftment 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 anesthesia, 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 principal evaluation of the efficiency of the graft will be based on the
      functional quality of the pharyngeal propulsion as determined by fibroscopy and
      videofluoroscopy 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 evaluation will include a clinical examination at each
      visit consisting of the examination of the pharynx in order to confirm the absence of muscle
      tumors and a cervical palpation in order to determine the volume of the muscle and to survey
      the site of myoblasts implantation. A rigid tube pharyngeal endoscopy which will be carried
      out under general anesthesia 6 to 12 months after the graft in case of abnormal pharynx at
      fibroscopy. 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 videofluoroscopy of swallowing will be
      carried out at 2 months then at 1 and 2 years after the graft.

      Risks and Benefits:

      The principal benefits to the patients which could be envisioned by this procedure is a delay
      in the deterioration of the pharyngeal 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 inflammatory reaction, the
      appearance of a tumor or the lack of improvement of the symptoms associated with the disease.

      A parallel preclinical study has been carried out in the dog in order to evaluate the
      tolerance and feasibility of the procedure for autografting myoblasts in the pharyngeal
      muscles.
    

Intervention name(s): Autologous myoblasts transplantation and myotomy
Intervention type(s): Procedure
Intervention description(s): Graft of autologous cell muscles (myoblasts) isolated from unaffected limb muscles into the pharyngeal muscles of patients diagnosed as suffering from OPMD and surgical procedure (myotomy)
Other intervention name(s): autograft and surgery
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Oculopharyngeal muscular dystrophy; Swallowing disorders, dysphagia; Pharyngeal propulsion; Upper oesophageal sphincter; Cricopharyngeal muscle; Autologous myoblasts; Autograft; Myotomy of the upper oesophageal sphincter; Fibroscopy of swallowing; Videofluoroscopy of swallowing