Stereotactic brain injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer's disease dementia: A phase 1 clinical trial

Hee Jin Kim, Sang Won Seo, Jong Wook Chang, Jung Il Lee, Chi Hun Kim, Juhee Chin, Soo Jin Choi, Hunki Kwon, Hyuk Jin Yun, Jong Min Lee, Sung Tae Kim, Yearn Seong Choe, Kyung-Han Lee, Duk L Na, Hee Jin Kim, Sang Won Seo, Jong Wook Chang, Jung Il Lee, Chi Hun Kim, Juhee Chin, Soo Jin Choi, Hunki Kwon, Hyuk Jin Yun, Jong Min Lee, Sung Tae Kim, Yearn Seong Choe, Kyung-Han Lee, Duk L Na

Abstract

Introduction: We conducted a phase 1 clinical trial in nine patients with mild-to-moderate Alzheimer's disease to evaluate the safety and dose-limiting toxicity of stereotactic brain injection of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs).

Methods: The low- (n = 3) and high-dose (n = 6) groups received a total of 3.0 × 106 cells/60 μL and 6.0 × 106 cells/60 μL, respectively, into the bilateral hippocampi and right precuneus.

Results: No patient showed serious adverse events including fever during the 24-month follow-up period. During the 12-week follow-up period, the most common acute adverse event was wound pain from the surgical procedure (n = 9), followed by headache (n = 4), dizziness (n = 3), and postoperative delirium (n = 3). There was no dose-limiting toxicity.

Discussion: Administration of hUCB-MSCs into the hippocampus and precuneus by stereotactic injection was feasible, safe, and well tolerated. Further trials are warranted to test the efficacy.

Clinical trial registration: ClinicalTrial.gov identifier NCT01297218 and NCT01696591.

Keywords: Alzheimer's disease; Hippocampus; Mesenchymal stem cell; Precuneus; Stereotactic injection.

Figures

Fig. 1
Fig. 1
Intraoperative navigation–guided stereotactic administration of hUCB-MSCs. hUCB-MSCs were injected into the right and left hippocampus and right precuneus at four sites (5-mm intervals) along the inserted trajectory while retracting the cannula (A). However, in six of nine patients, the fourth injection was located on the temporal horn of the lateral ventricle, probably due to substantial hippocampal atrophy. In these cases, the omitted doses were injected into the right precuneus, resulting in three injection sites in each hippocampus and six sites in the right precuneus (B). An example of stereotactic administration of hUCB-MSCs into the left hippocampus (C). Each patient received 12 injections for a total of 3.0 × 106 cells/60 μL in the low dose group or 6.0 × 106 cells/60 μL in the high dose group. Abbreviation: hUCB-MSCs, human umbilical cord blood–derived mesenchymal stem cells.

References

    1. Caplan A.I. Mesenchymal stem cells. J Orthop Res. 1991;9:641–650.
    1. Kim J.Y., Kim D.H., Kim J.H., Lee D., Jeon H.B., Kwon S.J. Soluble intracellular adhesion molecule-1 secreted by human umbilical cord blood-derived mesenchymal stem cell reduces amyloid-beta plaques. Cell Death Differ. 2012;19:680–691.
    1. Kim J.Y., Kim D.H., Kim D.S., Kim J.H., Jeong S.Y., Jeon H.B. Galectin-3 secreted by human umbilical cord blood-derived mesenchymal stem cells reduces amyloid-beta 42 neurotoxicity in vitro. FEBS Lett. 2010;584:3601–3608.
    1. Lee H.J., Lee J.K., Lee H., Shin J.W., Carter J.E., Sakamoto T. The therapeutic potential of human umbilical cord blood-derived mesenchymal stem cells in Alzheimer's disease. Neurosci Lett. 2010;481:30–35.
    1. Venkataramana N.K., Kumar S.K., Balaraju S., Radhakrishnan R.C., Bansal A., Dixit A. Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson's disease. Transl Res. 2010;155:62–70.
    1. Lee P.H., Lee J.E., Kim H.S., Song S.K., Lee H.S., Nam H.S. A randomized trial of mesenchymal stem cells in multiple system atrophy. Ann Neurol. 2012;72:32–40.
    1. Kim H.Y., Kim H., Oh K.W., Oh S.I., Koh S.H., Baik W. Biological markers of mesenchymal stromal cells as predictors of response to autologous stem cell transplantation in patients with amyotrophic lateral sclerosis; an investigator-initiated trial and in vivo study. Stem Cells. 2014;32:2724–2731.
    1. Karussis D., Karageorgiou C., Vaknin-Dembinsky A., Gowda-Kurkalli B., Gomori J.M., Kassis I. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol. 2010;67:1187–1194.
    1. Rafii M.S., Baumann T.L., Bakay R.A., Ostrove J.M., Siffert J., Fleisher A.S. A phase1 study of stereotactic gene delivery of AAV2-NGF for Alzheimer's disease. Alzheimers Dement. 2014;10:571–581.
    1. Mintun M.A., Larossa G.N., Sheline Y.I., Dence C.S., Lee S.Y., Mach R.H. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology. 2006;67:446–452.
    1. Thal D.R., Rub U., Orantes M., Braak H. Phases of abeta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58:1791–1800.
    1. Braak H., Alafuzoff I., Arzberger T., Kretzschmar H., Del Tredici K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol. 2006;112:389–404.
    1. Cavanna A.E., Trimble M.R. The precuneus: A review of its functional anatomy and behavioural correlates. Brain. 2006;129:564–583.
    1. Noh Y., Lee Y., Seo S.W., Jeong J.H., Choi S.H., Back J.H. A new classification system for ischemia using a combination of deep and periventricular white matter hyperintensities. J Stroke Cerebrovasc Dis. 2014;23:636–642.
    1. Karas G., Scheltens P., Rombouts S., van Schijndel R., Klein M., Jones B. Precuneus atrophy in early-onset Alzheimer's disease: A morphometric structural MRI study. Neuroradiology. 2007;49:967–976.
    1. Lee M.W., Jang I.K., Yoo K.H., Sung K.W., Koo H.H. Stem and progenitor cells in human umbilical cord blood. Int J Hematol. 2010;92:45–51.
    1. Lee O.K., Kuo T.K., Chen W.M., Lee K.D., Hsieh S.L., Chen T.H. Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood. 2004;103:1669–1675.
    1. Gluckman E., Broxmeyer H.A., Auerbach A.D., Friedman H.S., Douglas G.W., Devergie A. Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med. 1989;321:1174–1178.
    1. McKhann G., Drachman D., Folstein M., Katzman R., Price D., Stadlan E.M. Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984;34:939–944.
    1. Fazekas F., Kleinert R., Offenbacher H., Schmidt R., Kleinert G., Payer F. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology. 1993;43:1683–1689.
    1. McKhann G.M., Knopman D.S., Chertkow H., Hyman B.T., Jack C.R., Kawas C.H. The diagnosis of dementia due to Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:263–269.
    1. Vanderstichele H., Bibl M., Engelborghs S., Le Bastard N., Lewczuk P., Molinuevo J.L. Standardization of preanalytical aspects of cerebrospinal fluid biomarker testing for Alzheimer's disease diagnosis: A consensus paper from the Alzheimer's Biomarkers Standardization Initiative. Alzheimers Dement. 2012;8:65–73.
    1. Lalu M.M., McIntyre L., Pugliese C., Fergusson D., Winston B.W., Marshall J.C. Safety of cell therapy with mesenchymal stromal cells (SafeCell): A systematic review and meta-analysis of clinical trials. PLoS One. 2012;7:e47559.
    1. Ikonomovic M.D., Klunk W.E., Abrahamson E.E., Mathis C.A., Price J.C., Tsopelas N.D. Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease. Brain. 2008;131:1630–1645.
    1. Echavarri C., Burgmans S., Caballero M.C., Garcia-Bragado F., Verhey F.R., Uylings H.B. Co-occurrence of different pathologies in dementia: Implications for dementia diagnosis. J Alzheimers Dis. 2012;30:909–917.
    1. Lim A., Tsuang D., Kukull W., Nochlin D., Leverenz J., McCormick W. Clinico-neuropathological correlation of Alzheimer's disease in a community-based case series. J Am Geriatr Soc. 1999;47:564–569.
    1. Morris J.C., Edland S., Clark C., Galasko D., Koss E., Mohs R. The consortium to establish a registry for Alzheimer's disease (CERAD). Part IV. Rates of cognitive change in the longitudinal assessment of probable Alzheimer's disease. Neurology. 1993;43:2457–2465.
    1. Cho H., Jeon S., Kang S.J., Lee J.M., Lee J.H., Kim G.H. Longitudinal changes of cortical thickness in early- versus late-onset Alzheimer's disease. Neurobiol Aging. 2013;34 1921 e9–1921 e15.
    1. Schmidt C., Wolff M., Weitz M., Bartlau T., Korth C., Zerr I. Rapidly progressive Alzheimer disease. Arch Neurol. 2011;68:1124–1130.
    1. Soto M.E., Andrieu S., Arbus C., Ceccaldi M., Couratier P., Dantoine T. Rapid cognitive decline in Alzheimer's disease. Consensus paper. J Nutr Health Aging. 2008;12:703–713.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner