Open-labeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson's disease

Published:August 07, 2009DOI:
      Parkinson's disease (PD) is a progressive neurodegenerative disease for which stem cell research has created hope in the last few years. Seven PD patients aged 22 to 62 years with a mean duration of disease 14.7±7.56 years were enrolled to participate in the prospective, uncontrolled, pilot study of single-dose, unilateral transplantation of autologous bone-marrow-derived mesenchymal stem cells (BM-MSCs). The BM-MSCs were transplanted into the sublateral ventricular zone by stereotaxic surgery. Patients were followed up for a period that ranged from 10 to 36 months. The mean baseline “off” score was 65±22.06, and the mean baseline “on” score was 50.6±15.85. Three of 7 patients have shown a steady improvement in their “off”/“on” Unified Parkinson's Disease Rating Scale (UPDRS). The mean “off” score at their last follow-up was 43.3 with an improvement of 22.9% from the baseline. The mean “on” score at their last follow-up was 31.7, with an improvement of 38%. Hoehn and Yahr (H&Y) and Schwab and England (S&E) scores showed similar improvements from 2.7 and 2.5 in H&Y and 14% improvement in S&E scores, respectively. A subjective improvement was found in symptoms like facial expression, gait, and freezing episodes; 2 patients have significantly reduced the dosages of PD medicine. These results indicate that our protocol seems to be safe, and no serious adverse events occurred after stem-cell transplantation in PD patients. The number of patients recruited and the uncontrolled nature of the trial did not permit demonstration of effectiveness of the treatment involved. However, the results encourage future trials with more patients to demonstrate efficacy.


      7-AAD (7- amino actinomycin D), ADL (activities of daily living), bFGF (basic fibroblast growth factor), BM-MSC (bone-marrow-derived mesenchymal stem cell), COA (certificate of analysis), CT (computed tomography), DA (dopamine), DBS (deep brain stimulation), DPBS (Dulbecco's phosphate buffered saline), EDTA (ethylenediaminetetraacetic acid), FBS (fetal bovine serum), H&Y (Hoehn and Yahr), IEC (Institutional Ethics Committee), KO-DMEM (Knockout Dulbecco's Modified Eagle's Medium), MNC (mononuclear cell), PET (positron emission tomography), PD (Parkinson's disease), RT-PCR (reverse transcriptase-polymerase chain reaction), S&E (Schwab and England), SVZ (subventricular zone), UPDRS (Unified Parkinson Disease Rating Scale)
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        • Lang A.E.
        • Obeso J.A.
        Time to move beyond nigrostriatal dopamine deficiency in Parkinson's disease.
        Ann Neurol. 2004; 55: 761-765
        • Hely M.A.
        • Morris J.G.
        • Reid W.G.
        • et al.
        Sydney Multicenter Study of Parkinson's disease: non-L-dopa-responsive problems dominate at 15 years.
        Mov Disord. 2005; 20: 190-199
        • Shults C.W.
        • Oakes D.
        • Kieburtz K.
        • et al.
        Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline.
        Arch Neurol. 2002; 59: 1541-1550
        • Fahn S.
        • Oakes D.
        • Shoulson I.
        • et al.
        Levodopa and the progression of Parkinson's disease.
        N Engl J Med. 2004; 351: 2498-2508
        • Marsden C.D.
        • Parkes J.D.
        Success and problems of long-term levodopa therapy in Parkinson's disease.
        Lancet. 1977; 1: 345-349
        • Obeso J.A.
        • Rodriguez-Oroz M.C.
        • Rodriguez M.
        • et al.
        Pathophysiology of the basal ganglia in Parkinson's disease.
        Trends Neurosci. 2000; 23: S8-S19
        • Pifl C.
        • Schingnitz G.
        • Hornykiewicz O.
        Striatal and non-striatal neurotransmitter changes in MPTP-parkinsonism in rhesus monkey: the symptomatic versus the asymptomatic condition.
        Neurochem Int. 1992; 20: 295S-297S
        • Sossi V.
        • Fuente-Fernandez R.
        • Holden J.E.
        • Schulzer M.
        • Ruth T.J.
        • Stoessl J.
        Changes of dopamine turnover in the progression of Parkinson's disease as measured by positron emission tomography: their relation to disease-compensatory mechanisms.
        J Cereb Blood Flow Metab. 2004; 24: 869-876
        • Calabresi P.
        • Mercuri N.B.
        • Sancesario G.
        • Bernardi G.
        Electrophysiology of dopaminedenervated striatal neurons. Implications for Parkinson's disease.
        Brain. 1993; 116: 433-452
        • Bezard E.
        • Boraud T.
        • Bioulac B.
        • Gross C.E.
        Involvement of the subthalamic nucleus in glutamatergic compensatory mechanisms.
        Eur J Neurosci. 1999; 11: 2167-2170
        • Bezard E.
        • Dovero S.
        • Prunier C.
        • et al.
        Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- lesioned macaque model of Parkinson's disease.
        J Neurosci. 2001; 21: 6853-6861
        • Alvarez-Buylla A.
        • Garcia-Verdugo J.M.
        • Tramonti A.D.
        A unified hypothesis on the lineage of neural stem cells.
        Nat Rev Neurosci. 2001; 2: 287-293
        • Olanow C.W.
        • Kordower J.H.
        • Freeman T.B.
        Fetal nigral transplantation as a therapy for Parkinson's disease.
        Trends Neurosci. 1996; 19: 102-109
        • Freed C.R.
        • Greene P.E.
        • Breeze R.E.
        • et al.
        Transplantation of embryonic dopamine neurons for severe Parkinson's disease.
        N Engl J Med. 2001; 344: 710-719
        • Pal R.
        • Hanwate M.
        • Jan M.
        • Totey S.
        Phenotypic and functional comparison of optimum culture conditions for upscaling of bone marrow-derived mesenchymal stem cells.
        J Tissue Eng Regen Med. 2009; 3: 163-174
        • Fahn S.
        • Marsden C.D.
        • Calne D.B.
        • Goldstein M.
        Recent developments in Parkinson's disease.
        Macmillan Healthcare Information, Florham Park, NJ1987 (153–163)
        • Langston J.W.
        • Widner H.
        • Goetz C.G.
        • et al.
        Core assessment program for intracerebral transplantations (CAPIT).
        Mov Disord. 1992; 7: 2-13
        • Eeden V.D.
        • Stephen K.
        • Tanner C.M.
        • et al.
        Incidence of Parkinson's Disease: Variation by age, gender, and race/ethnicity.
        Am J Epidemiol. 2003; 157: 1015-1022
        • Morrison S.J.
        • Uchida N.
        • Weissman I.L.
        The biology of hematopoietic stem cells.
        Ann Rev Cell Dev Biol. 1995; 11: 35-71
        • Deans R.J.
        • Moseley A.M.
        Mesenchymal stem cells: biology and potential clinical uses.
        Exp Hematol. 2000; 28: 875-884
        • Wenning G.K.
        • Odin P.
        • Morrish P.
        • et al.
        Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson's disease.
        Ann Neurol. 1997; 42: 95-107
        • Hauser R.A.
        • Freeman T.B.
        • Snow B.J.
        • et al.
        Long-term evaluation of bilateral fetal nigral transplantation in Parkinson's disease.
        Arch Neurol. 1999; 56: 179-187
        • Kordower J.H.
        • Freeman T.B.
        • Snow B.J.
        • et al.
        Neuropathological evidence of graft survival and striatal reinnervation after transplantation of fetal mesencephalic tissue in a patient with Parkinson's disease.
        N Engl J Med. 1995; 332: 1118-1124
        • Olanow C.W.
        • Goetz C.G.
        • Kordower J.H.
        • et al.
        A double-blind controlled trial of bilateral fetal nigral transplantation in Parkinson's Disease.
        Ann Neurol. 2003; 54: 403-414
        • Lindvall O.
        • Sawle G.
        • Widner H.
        • et al.
        Evidence of long-term survival and function of dopaminergic grafts in progressive Parkinson's disease.
        Ann Neurol. 1994; 35: 172-180
        • Freed C.R.
        • Breeze R.E.
        • Rosenberg N.L.
        • et al.
        Survival of implanted fetal dopamine cells and neurologic improvement 12 to 46 months after transplantation for Parkinson's disease.
        N Engl J Med. 1992; 327: 1549-1555
        • Doetsch F.
        • Alvarez-Buylla A.
        Network of tangential pathways for neuronal migration in adult mammalian brain.
        Proc Natl Acad Sci USA. 1996; 93: 14895-14900
        • Altman J.
        Autoradiographic and histological studies of postnatal neurogenesis. IV. Cell proliferation and migration in the anterior forebrain, with special reference to persisting neurogenesis in the olfactory bulb.
        J Comp Neurol. 1969; 137: 433-458
        • Lois C.
        • Alvarez-Buylla A.
        Long-distance neuronal migration in the adult mammalian brain.
        Science. 1994; 264: 1145-1148
        • Kornack D.R.
        • Rakic P.
        The generation, migration, and differentiation of olfactory neurons in the adult primate brain.
        Proc Natl Acad Sci USA. 2001; 98: 4752-4757
        • Weiss S.
        • Dunne C.
        • Hewson J.
        • et al.
        Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis.
        J Neurosci. 1996; 16: 7599-7609
        • Temple S.
        • Alvarez-Buylla A.
        Stem cells in the adult mammalian central nervous system.
        Curr Opin Neurobiol. 1999; 9: 135-141
        • Gage F.H.
        Mammalian neural stem cells.
        Science. 2000; 287: 1433-1438
        • Pearce R.K.B.
        • Jackson M.
        • Smith L.
        • Jenner P.
        • Marsden C.D.
        Chronic L-dopa administration induces dyskinesias in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinetreated common marmoset (Callithrix Jacchus).
        Mov Disord. 1995; 10: 731-740
        • Shetty P.
        • Ravindran G.
        • Sarang S.
        • Thakur A.
        • Rao H.S.
        • Viswanathan C.
        Clinical grade mesenchymal stem cells transdifferentiated under xenofree conditions alleviates motor deficiencies in a rat model of Parkinson's disease.
        Cell Biol Int. 2009; 33: 830-838
        • Levy Y.S.
        • Bahat-Stroomza M.
        • Barzilay R.
        • et al.
        Regenerative effect of neural induced human mesenchymal stromal cells in rat models of Parkinson's disease.
        Cytotherapy. 2008; 10: 340-352
        • Trzaska K.A.
        • Kuzhikandathil E.V.
        • Rameshwar P.
        Specification of a dopaminergic phenotype from adult human mesenchymal stem cells.
        Stem Cells. 2007; 25: 2797-2808
        • Pisati F.
        • Bossolasco P.
        • Meregalli M.
        • et al.
        Induction of neurotrophin expression via human adult mesenchymal stem cells: implication for cell therapy in neurodegenerative disease.
        Cell Transplantation. 2007; 16: 41-55
        • Le Blanc K.
        • Ringden O.
        Mesenchymal stem cell properties and role in clinical bone marrow transplantation.
        Curr Opin Immunol. 2006; 18: 586-591
        • Deng Y.B.
        • Liu X.G.
        • Liu Z.G.
        • et al.
        Implantation of BM Mesenchymal stem cells into injured spinal cord elicit de novo neurogenesis and functional recovery: evidence from a study in rhesus monkey.
        Cytotherapy. 2006; 8: 210-214