title: Restoration of anal sphincter function after myoblast cell therapy in incontinent rats.
abstract: Fecal incontinence (FI) remains a socially isolating condition with profound impact on quality of life for which autologous myoblast cell therapy represents an attractive treatment option. We developed an animal model of FI and investigated the possibility of improving sphincter function by intrasphincteric injection of syngeneic myoblasts. Several types of anal cryoinjuries were evaluated on anesthetized Fischer rats receiving analgesics. The minimal lesion yielding sustainable anal sphincter deficiency was a 90° cryoinjury of the sphincter, repeated after a 24-h interval. Anal sphincter pressure was evaluated longitudinally by anorectal manometry under local electrostimulation. Myoblasts were prepared using a protocol mimicking a clinical-grade process and further transduced with a GFP-encoding lentiviral vector before intrasphincteric injection. Experimental groups were uninjured controls, cryoinjured + PBS, and cryoinjured + myoblasts (different doses or injection site). Myoblast injection was well tolerated. Transferred myoblasts expressing GFP integrated into the sphincter and differentiated in situ into dystrophin-positive mature myofibers. Posttreatment sphincter pressures increased over time. At day 60, pressures in the treated group were significantly higher than those of PBS-injected controls and not significantly different from those of normal rats. Longitudinal follow-up showed stability of the therapeutic effect on sphincter function over a period of 6 months. Intrasphincteric myoblast injections at the lesion borders were equally as effective as intralesion administration, but an injection opposite to the lesion was not. These results provide proof of principle for myoblast cell therapy to treat FI in a rat model. This strategy is currently being evaluated in humans in a randomized double-blind placebo-controlled clinical trial.
authors.affiliation: Inserm, U905, Rouen, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Bisson
authors.forename: Manuel
authors.initials: M
authors.lastname: Fréret
authors.forename: Laurent
authors.initials: L
authors.lastname: Drouot
authors.forename: Laetitia
authors.initials: L
authors.lastname: Jean
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Le Corre
authors.forename: Guillaume
authors.initials: G
authors.lastname: Gourcerol
authors.forename: Christelle
authors.initials: C
authors.lastname: Doucet
authors.forename: Francis
authors.initials: F
authors.lastname: Michot
authors.forename: Olivier
authors.initials: O
authors.lastname: Boyer
authors.forename: Marek
authors.initials: M
authors.lastname: Lamacz
mesh_terms: D001003:Anal Canal / Q000473:pathology / Q000502:physiology*; D000818:Animals; D064987:Cell- and Tissue-Based Therapy; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004558:Electric Stimulation; D005242:Fecal Incontinence / Q000473:pathology / Q000628:therapy*; D005260:Female; D006801:Humans; D009119:Muscle Contraction; D032446:Myoblasts / Q000166:cytology / Q000637:transplantation*; D051381:Rats; D020127:Recovery of Function