An overview of domestic and international clinical trials for delivery of cellular therapies to the spinal cord.

Although varied, pathological afflictions to the spinal cord have limited therapeutic options and often carry a poor prognosis. This range includes traumatic (eg, spinal cord injury), inflammatory (eg, multiple sclerosis), and neurodegenerative (eg, amyotrophic lateral sclerosis [ALS], spinal muscular atrophy [SMA]) conditions. Numerous therapies have been tested for the treatment of spinal cord injury in a combination of domestic and international preclinical and clinical studies. None has demonstrated clinical efficacy and been approved for use. The current standard of clinical practice for traumatic spinal injury remains surgical decompression and spinal stabilization. Multiple sclerosis, an autoimmune condition in which the myelin protein is thought to provoke an immune response, is modified by both nonspecific immunomodulators such as corticosteroids and more targeted agents such as Tysabri (Natalizumab, Biogen Idec). This occurs at the risk of sometimes severe off-target effects and fails to restore lost myelination in disease-affected plaques. Finally, degenerative pathologies such as ALS and SMA portend a course of progressively worsening neurological function and a fatal prognosis. ALS is affected only minimally by currently available therapeutics, with Rilutek (Riluzole, Sanofi-Aventis) improving life expectancy by a few months. Therapies for SMA are focused solely on symptom alleviation. It is with this background that cellular therapies have been considered for the treatment of spinal cord afflictions. Table 1 itemizes the completed international trials (2001-2009) that have assessed the safety and efficacy of cellular therapeutics for traumatic and degenerative indications. These studies have set the precedent for the current domestic and international trials assessing the delivery of cellular therapeutics that are underway. Contemporary trials assessing cellular therapies for neurodegenerative, inflammatory, and traumatic spinal conditions are introduced. Sections are arranged according to therapy delivery route. Table 2 reviews ongoing cellular delivery trials that employ either an intravenous or intrathecal therapy delivery route. Table 3 explores ongoing or near-term trials that use direct intraspinal microinjection to deliver a cellular graft. Citation sources have included searches of the MedLine (www.pubmed.gov) and National Institutes of Health (www.clinicaltrials.gov) databases, as well as personal communications of the senior author. INTRAVENOUS DELIVERY Only 1 trial exploring the intravenous delivery of a cellular therapy for treatment of spinal pathology is currently underway, as shown in Table 2. Inclusion criteria include a pediatric population of 1 to 15 years of age, an incomplete or complete spinal cord injury, and an injury that occurred between 6 months and 4 years before treatment. Autologous bone marrow progenitor cells are harvested to a quantity of up to 5 mL/kg, are processed, and are given through a single intravenous infusion. The primary outcome measure is the American Spinal Injury Association (ASIA) classification assessment that is completed at 1, 30, and 180 days after transplantation. The same group recently completed a phase I trial assessing the safety of intravenous autologous bone marrow progenitor cell delivery for acute traumatic brain injury in a pediatric population followed up for 6 months. While noting the safety of the approach in this trial, the authors indicated that their choice of cellular graft was guided in part by (1) small bone marrow progenitor cell size preventing a pulmonary “first-pass” effect, (2) ease of availability, (3) lack of ethical concerns, (4) data supporting lack of bone marrow progenitor cell tumorigenicity, and (5) lack of a need for cell banking and scaling for autologous application. The authors cite numerous possible mechanisms of effect, which include an immunomodulatory and local antiinflammatory actions, as well as the paracrine secretion of growth factors and cytokines that may support an “at-risk” cellular population.