Human intrathecal transplantation of peripheral blood stem cells in amyotrophic lateral sclerosis

913 WE WRITE TO COMMENT BRIEFLY on the neurological literature on blood-derived neural stem cells, and to offer a case report regarding the safety of a simple procedure to introduce stem cells to the cerebrospinal fluid (CSF) compartment. For decades there has been evidence for cells of common neural and hematopoietic potential; this phenomenon was originally demonstrated by the presence of pluripotent cells resident in the adult brain that could form hematopoietic colonies in irradiated animals, as well as antigenic cross-reactivity between certain neural and hematopoietic cells (1–3). Recent studies have reproduced and confirmed the pleuripotency of neuro-hematopoietic cells, and showed that “blood can turn into brain” and vice-versa (4–6). Dr. W. Krivit at Harvard was the first to show that bone marrow transplantation (BMT) ameliorates some forms of central nervous system (CNS) genetic and metabolic disease (7), thought to be due to cellular margination and passage of the blood–brain barrier, which raised the intriguing idea of grafting blood cells directly to the human CNS. Indeed, administration of bone marrow-derived cells to the brain with neuronal engraftment has been demonstrated in animal models (8), and published reports now show blood stem cell differentiation along various neural lineages, including neurons and astrocytes. In an important clinical experiment conducted in Sweden, a group of patients received an intravenous (i.v.) label of bromodeoxyuridine (BrdU), which detects division of new cells. This work proved that neural progenitor cells exist in the brain of the adult human (9), thus generalizing an observation from primates and other animals that had generated much controversy, because it challenged a long-held tenet that brain cells could not be replenished or regenerate in situ. The precise source of neural progenitor cells is still a matter of debate and speculation, but the consensus is that they appear to be enriched around vascular tissues in the forebrain subventricular zone, the ependyma, and the dentate gyrus of the hippocampus. Given the close association between the vasculature and the sources of neural stem cells (10), one possibility is that neural stem cells arise in the adult human brain both from primordial brain stem cells and from migratory hematopoietic-derived cells. Considering the lack of effective drugs for amyotrophic lateral sclerosis (ALS) and accumulating evidence that primordial blood-derived cells can adopt a neuronal or glial fate, in 1999 we began exploring a blood stem cell selection protocol for application to ALS, in parallel with long-term plans for other experimental approaches. The objective was to bring to the clinic any promising drug or treatment protocol that had already been approved for human use. CD341 stem cell selection protocols are widely used in bone marrow transplants and are approved by the U.S. Food and Drug Administration (FDA), although clinical application for ALS is “off-label.” Immune ablation followed by BMT has already been performed in studies on multiple sclerosis and other primary CNS conditions; however, the mechanism we anticipated is one of cell grafting, CNS-specific differentiation, and local trophic effects, rather than the reconstitution of pharmacologically depleted immune cells. To demonstrate safety and generate preliminary data in support of dosing and method of deliver, we transplanted adult human marrow and fetal CD341 cells directly into the nonimmunosuppressed monkey spinal cord and intrathecal space. The monkeys underwent laminectomies, and xenogeneic human cells were introduced to the midline of the dorsal spinal cord at multiple sites using a Hamilton syringe and 30-gauge needle, without adverse behavioral or serological responses. The limited work available in the literature on cord blood transplants to superoxide dismutase (SOD1) mice also supported our ra