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NEUROLOGY 2008;71:1326-1334
© 2008 American Academy of Neurology

Hematopoietic stem cell transplantation in patients with sporadic amyotrophic lateral sclerosis

S. H. Appel, MD, J. I. Engelhardt, MD, J. S. Henkel, PhD, L. Siklos, PhD, D. R. Beers, PhD, A. A. Yen, MD, E. P. Simpson, MD, Y. Luo, G. Carrum, MD, H. E. Heslop, MD, M. K. Brenner, PhD, MBBCh and U. Popat, MD

From the Department of Neurology (S.H.A., J.S.H., D.R.B., A.A.Y., E.P.S.), Methodist Neurological Institute, Houston, TX; Department of Neurology (J.I.E.), University of Szeged, Hungary; Institute of Biophysics (L.S.), Biological Research Center, Szeged, Hungary; Department of Pathology (Y.L.), Methodist Hospital, Houston, TX; Center for Cell and Gene Therapy (G.C., H.E.H., M.K.B., U.P.), Methodist Hospital and Baylor College of Medicine, Houston, TX; and University of Texas M. D. Anderson Cancer Center (U.P.), Houston, TX.

Address correspondence and reprint requests to Dr. Stanley H. Appel, Department of Neurology, Methodist Neurological Institute, 6560 Fannin St., Suite ST-802, Houston, TX 77030 sappel{at}tmhs.org

Background: Amyotrophic lateral sclerosis (ALS), an inexorably progressive motoneuron disease, is accompanied by significantly increased markers of inflammation. These inflammatory constituents could protect, harm, do neither, or do both.

Objective: Allogeneic hematopoietic stem cell transplantation (HSCT) was performed in patients with sporadic ALS to suppress neuroinflammation and improve clinical outcomes after CNS engraftment.

Methods: Six patients with definite ALS received total body irradiation followed by peripheral blood HSCT infusion from human leukocyte antigen identically matched sibling donors. Disease progression and survival were assessed monthly and compared with matched historic database patients. Autopsy samples from brain and spinal cord were examined immunohistochemically and by quantitative reverse-transcriptase polymerase chain reaction. Donor-derived DNA in brain and spinal cord tissue was evaluated for the extent of chimerism.

Results: No clinical benefits were evident. Four patients were 100% engrafted; postmortem tissue examination in two of the 100% engrafted patients demonstrated 16% to 38% donor-derived DNA at sites with motoneuron pathology, which may correspond to the observed increased CD68 or CD1a-positive cells. Neither donor DNA nor increased cell numbers were found in several unaffected brain regions. A third minimally engrafted patient had neither donor DNA nor increased infiltrating cells in the CNS.

Conclusions: This study demonstrates that peripheral cells derived from donor hematopoietic stem cells can enter the human CNS primarily at sites of motoneuron pathology and engraft as immunomodulatory cells. Although unmodified hematopoietic stem cells did not benefit these sporadic amyotrophic lateral sclerosis patients, such cells may provide a cellular vehicle for future CNS gene therapy.

Abbreviations: AALS = Appel amyotrophic lateral sclerosis; ALS = amyotrophic lateral sclerosis; Arsa–/– = arylsulfatase deficient; FVC = forced vital capacity; GVHD = graft-versus-host disease; HCST = hematopoietic stem cell transplantation; HLA = human leukocyte antigen; MCP-1 = monocyte chemoattractant protein 1; mRNA = messenger RNA; mSOD1 = mutant Cu2+/Zn2+ superoxide dismutase; NNDC = nonneurologic disease control; RT-PCR = reverse-transcriptase polymerase chain reaction; sALS = sporadic amyotrophic lateral sclerosis.

J.I.E. and L.S. were supported in part by the Hungarian Scientific Research Fund.

Disclosure: The authors report no disclosures.

Received March 31, 2008. Accepted in final form July 7, 2008.






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