Translational applications of placental dervided mesenchymal stem cells for the treatment of spina bifida: a canine model

Abstract

Background & Aim The canine is increasingly recognized as a valuable pre-clinical large animal model for many human diseases including cancer, respiratory disease, and inflammatory disease. Like humans, canines live in similar conditions, receive long term medical care, and develop congenital diseases including spina bifida (SB). Canine SB clinically presents very similarly to human SB, and English bulldogs in particular have a high incidence of naturally-occurring SB. Placental mesenchymal stem cells (PMSCs) are being investigated as an adjunct to prenatal repair of SB; however, similar treatments have not been explored for postnatal repair. English bulldogs could serve as the first postnatal animal model of SB. The goal of this study is to evaluate canine PMSCs (cPMSCs) to test their efficacy as a postnatal therapy in a naturally-occurring large animal disease model. If successful, this approach may be a significant step toward translating this therapy to human patients, and may offer the first regenerative treatment for their canine companions born with SB. Methods, Results & Conclusion To date, we have enrolled four 9-week-old English bulldogs with SB defects confirmed by neurological evaluation and magnetic resonance imaging (MRI). Each dog underwent a multi-segment laminectomy, coupled with transplant of allogeneic cPMSCs embedded in hydrogel and extracellular matrix (ECM) scaffold. One-year follow-up has been completed on two study animals and the remaining two animals are currently being evaluated at 8 weeks post-treatment. The first two dogs enrolled were initially ambulatory with notable abnormal gaits and incontinence. MRI revealed L7-S1 defects of varying severity. One MRI also showed a large syringohydromyelnia involving the lumbar spinal cord. Electrophysiologic testing revealed low-normal conduction velocity for both motor and sensory hindlimb nerves. Both dogs recovered from posterior laminectomy and cPMSC implantation uneventfully. Following treatment both dogs showed improved ambulatory gaits. No significant adverse events occurred in either dog by 12 months. Two additional dogs have been enrolled and are currently being evaluated. Postnatal treatment of a naturally-occurring canine model of SB with allogeneic cPMSCs is clinically feasible and appears safe. Further studies are currently being performed to evaluate efficacy.The findings from this study suggest that naturally-occuring canine SB is a valuable translational model to evaluate PMSC postnatal therapy.