Sains Malaysiana 50(5)(2021): 1381-1392

http://doi.org/10.17576/jsm-2021-5005-17

Down Syndrome and Cell Therapy: A Review

(Sindrom Down dan Terapi Sel: Suatu Ulasan)

NORIZAM SALAMT¹, RUSZYMAH HAJI IDRUS¹ & NOOR WAHIDAH MOHD NASRI^1,2*

¹Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur, Malaysia

²Department of Nursing, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Bandar Tun Razak, 56000 Cheras, Kuala Lumpur, Malaysia

Diserahkan: 22 Oktober 2019/Diterima: 28 September 2020

ABSTRACT

Cell therapy has been considered as an alternative treatment for many diseases, including Down syndrome (DS). However, this treatment remained debatable due to insufficient clinical data.  Therefore, this study aims to identify and evaluate studies on the potential of cell therapy in improving the quality of life of DS patients. Relevant English articles and snowball sampling from Science Direct and PubMed (published until August 2019) on the effects of cell therapy on DS was retrieved. Only original articles on the effect of cell therapy in DS patients or Ts65Dn (trisomic) mice were selected. Two independent reviewers reviewed the articles with selective inclusion criteria using a standard data extraction form. Cell therapy showed no significant findings on the physical appearance, cognitive function, social, and behavior skills of DS patients. Interestingly, implantation of murine neural stem cell (mNSC) or murine neural progenitor cell (mNPC) showed better cell survival and response towards brain injury, decrease tau + granules and increase granules density in the dentate gyrus in the trisomic mice. mNSC/mNPC in mice brain was found to be able to migrate to the sites of the injury following chemokine signals and eventually provide neuroprotection and promote axonal growth. To conclude, mNSC/mNPC implantation could be considered as an alternative treatment for DS or DS with early onset of Alzheimer Disease (AD).

Keywords: Cell therapy; Down syndrome; sicca cell therapy; trisomy 21

ABSTRAK

Rawatan terapi sel telah dipertimbangkan sebagai rawatan alternatif pelbagai penyakit, termasuklah Sindrom Down (SD). Walau bagaimanapun, keberkesanan terapi sel masih dibincangkan kerana kekurangan data klinikal. Maka, kami berazam untuk mengenal pasti dan menilai kajian ke atas potensi terapi sel dalam meningkatkan kualiti hidup pesakit SD. Makalah bahasa Inggeris berkaitan dan persampelan snowball atau hand selected daripada Science Direct dan Pubmed (diterbitkan sehingga Ogos 2019) berkaitan kesan terapi sel ke atas SD telah dijalankan. Hanya makalah asal tentang kesan terapi sel pada pesakit SD atau mencit Ts65Dn (trisomi) telah dipilih. Dua orang penilai bebas telah menilai makalah dengan kriteria rangkuman pilihan menggunakan borang pengekstrakan data lazim. Terapi sel menunjukkan keputusan tanpa implikasi terhadap penampilan fizikal, fungsi kognitif dan kemahiran sosial serta tingkah laku pesakit SD. Menariknya, implan sel stem neuron murin (mNSC) atau sel progenitor neuron murin (mNPC) menunjukkan kebolehan sel untuk terus hidup dengan lebih baik dan bertindak balas terhadap kecederaan otak, mengurangkan granul tau+ dan meningkatkan ketumpatan granul di girus dentat pada mencit trisomi. mNSC/mNPC pada otak mencit menunjukkan kebolehan untuk bergerak ke bahagian yang mengalami kecederaan berpandukan isyarat kemokin dan seterusnya melindungi neuron dan menggalakkan pertumbuhan akson. Kesimpulannya, pengimplanan mNSC/mNPC boleh dijadikan sebagai rawatan alternatif untuk pesakit SD atau mengurangkan simptom penyakit Alzhemeir dalam kalangan pesakit SD.

Kata kunci: Sindrom Down; terapi sel; terapi sel sicca; trisomi 21

RUJUKAN

Bardon, L.M. 1964. Sicca cell treatment in mongolism. Lancet 2(7353): 234-235.

Belichenko, P.V., Kleschevnikov, A.M., Masliah, E., Wu, C., Takimoto-Kimura, R., Salehi, A. & Mobley, W.C. 2009. Excitatory-inhibitory relationship in the fascia dentata in the ts65dn mouse model of down syndrome. Journal of Comparative Neurology 512(4): 453-466.

Berger, I., Ahmad, A., Bansal, A., Kapoor, T., Sipp, D. & Rasko, J.E.J. 2016. Global distribution of businesses marketing stem cell-based interventions. Cell Stem Cell 19(2): 158-162.

Bianchi, P., Ciani, E., Guidi, S., Trazzi, S., Felice, D. & Grossi, G. 2010. Early pharmacotherapy restores neurogenesis and cognitive performance in the ts65dn mouse model for down syndrome. Journal of Neuroscience 30(26): 8769-8779.

Bimonte-Nelson, H.A., Hunter, C.L., Nelson, M.E. & Granholm, A.C. 2003. Frontal cortex BDNF levels correlate with working memory in an animal model of down syndrome. Behavioral Brain Research 139(1-2): 47-57.

Bjugstad, K.B., Teng, Y.D., Redmond, Jr. D.E., Elsworth, J.D., Roth, R.H. & Cornelius, S.K. 2008. Human neural stem cells migrate along the nigrostriatal pathway in a primate model of Parkinson's disease. Experimental Neurology 211(2): 362-369.

Black, D.B., Kato, J.G. & Walker, G.W.H. 1966. A study of improvement in mentally retarded children accruing from sicca cell therapy. American Journal of Mental Deficiency 70(4): 499-508.

Bloom, G.S. 2014. Amyloid-β and tau: The trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurology 71(4): 505-508.

Bouab, M., Paliouras, G.N., Aumont, A., Forest-Berard, K. & Fernandes, K.J. 2011. Aging of the subventricular zone neural stem cell niche: Evidence for quiescence-associated changes between early and mid-adulthood. Neuroscience 173: 135-149.

Bosch, M., Pineda, J.R., Sunol, C., Petriz, J., Cattaneo, E. & Alberch, J. 2004. Induction of gabaergic phenotype in a neural stem cell line for transplantation in an excitotoxic model of Huntington's disease. Experimental Neurology 190(1): 42-58.

Caraci, F., Iulita, M.F., Pentz, R., Aguilar, L.F., Orciani, C. & Barone, C. 2017. Searching for new pharmacological targets for the treatment of Alzheimer’s disease in down syndrome. European Journal of Pharmacology 817: 7-19.

Chakrabarti, L., Scafidi, J., Gallo, V. & Haydar, T.F. 2011. Environmental enrichment rescues postnatal neurogenesis defect in the male and female ts65dn mouse model of down syndrome. Developmental Neuroscience 33(5): 428-441.

Coghlan, A. 2017. Clinic Claims Stem Cells Treat Down’s Syndrome. New Scientist. Accessed on 1 February 2017.

Costa, A.C. & Grybko, M.J. 2005. Deficits in hippocampal CA1 LTP induced by TBS but not HFS in the Ts65Dn mouse: A model of down syndrome. Neuroscience Letter 382(3): 317-322.

Deutsch, S.I., Rosse, R.B. & Lakshman, R.M. 2006. Dysregulation of tau phosphorylation is a hypothesized point of convergence in the pathogenesis of Alzheimer’s disease, frontotemporal dementia and schizophrenia with therapeutic implications. Progress in Neuro-Psychopharmacology & Biological Psychiatry 30(8): 1369-1380.

Dimayuga, F.O., Wang, C., Clar, J.M., Dimayuga, E.R., Dimayuga, V.M. & Bruce-Keller, A.J. 2007. SOD1 overexpression alters ROS production and reduces neurotoxic inflammatory signaling in microglial cells. Journal of Neuroimmunology 182(1-2): 89-99.

Ebert, A.D., Barber, A.E., Heins, B.M. & Svendsen, C.N. 2010. Ex vivo delivery of GDNF maintains motor function and prevents neuronal loss in a transgenic mouse model of Huntington's disease. Experimental Neurology 224(1): 155-162.

Elliott, E. & Ginzburg, I. 2006. The role of neurotrophins and insulin on tau pathology in Alzheimer’s disease. Reviews in the Neurosciences 17(6): 635-642.

Fisher, S.A., Doree, C., Mathur, A., Taggart, D.P. & Martin-Rendon, E. 2016. Stem cell therapy for chronic ischemic heart disease and congestive heart failure. Cochrane Database of Systematic Reviews (12): CD007888.

Foreman, P.J. & Ward, J. 1987. An evaluation of cell therapy in down syndrome. Journal of Paediatrics and Child Health 23(3): 151-156.

Frotscher, M. 1997. Dual role of Cajal-Retzius cells and reelin in cortical development. Cell and Tissue Research 290(2): 315-322.

Fuster-Matanzo, A., Llorens-Martín, M., Jurado-Arjona, J., Avila, J. & Hernández, F. 2012. Tau protein and adult hippocampal neurogenesis. Frontiers in Neuroscience 6: 1-6.

Glasson, E.J., Jacques, A., Wong, K., Bourke, J. & Leonard, H. 2016. Improved survival in down syndrome over the last 60 years and the impact of perinatal factors in recent decades. The Journal of Pediatrics 169: 214-220.

Gopalan, N., Mohd Noor, S.N. & Mohamed, M.S. 2017. Guidelines, policies, laws? how best to address the ethics of stem cell research in Malaysia. e-Proceeding of the 5th International Conference on Social Sciences Research. pp. 52-69.

Hattiangady, B., Shuai, B., Cai, J., Coksaygan, T., Rao, M.S. & Shetty, A.K. 2007. Increased dentate neurogenesis after grafting of glial restricted progenitors or neural stem cells in the aging hippocampus. Stem Cells 25(8): 2104-2117.

Inoue, M., Kajiwara, K., Yamaguchi, A., Kiyono, T., Samura, O. & Akutsu, H. 2019. Autonomous trisomic rescue of down syndrome cells. Laboratory Investigation 99(6): 885-897.

Insausti, A.M., Megias, M., Crespo, D., Cruz-Orive, L.M., Dierssen, M. & Vallina, T.F. 1998. Hippocampal volume and neuronal number in ts65dn mice: A murine model of down syndrome. Neuroscience Letter 253(3): 175-178.

Jing, M., Shingo, T., Yasuhara, T., Kondo, A., Morimoto, T. & Wang, F. 2009. The combined therapy of intrahippocampal transplantation of adult neural stem cells and intraventricular erythropoietin-infusion ameliorates spontaneous recurrent seizures by suppression of abnormal mossy fiber sprouting. Brain Research 1295: 203-217.

Kamei, N., Tanaka, N., Oishi, Y., Hamasaki, T., Nakanishi, K. & Sakai, N. 2007. BDNF, NT-3, and NGF released from transplanted neural progenitor cells promote corticospinal axon growth in organotypic cocultures. Spine 32(12): 1272-1278.

Kazma, M., Izrael, M., Revel, M., Chebath, J. & Yanai, J. 2010. Survival, differentiation, and reversal of heroin neurobehavioral teratogenicity in mice by transplanted neural stem cells derived from embryonic stem cells. Journal of Neuroscience Research 88(2): 315-323.

Kern, D.S., Maclean, K.N., Jiang, H., Synder, E.Y., Sladek, Jr. J.R. & Bjugstad, K.B. 2011. Neural stem cells reduce hippocampal tau and reelin accumulation in aged ts65dn down syndrome mice. Cell Transplant 20(3): 371-379.

Kleschevnikov, A.M., Belichenko, P.V., Villar, A.J., Epstein, C.J., Malenka, R.C. & Mobley, W.C. 2004. Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of down syndrome. Journal of Neuroscience 24(37): 8153-8160.

Koutsoudaki, P.N., Papastefanaki, F., Stamatakis, A., Kouroupi, G., Xingi, E. & Stylianopoulou, F. 2016. Neural stem/progenitor cells differentiate into oligodendrocytes, reduce inflammation, and ameliorate learning deficits after transplantation in a mouse model of traumatic brain injury. GLIA 64(5): 763-779.

Lemaire, V., Lamarque, S., Le Moal, M., Piazza, P.V. & Abrous, D.N. 2006. Postnatal stimulation of the pups counteracts prenatal stress-induced deficits in hippocampal neurogenesis. Biological Psychiatry 59(9): 786-792.

Leverenz, J.B. & Raskind, M.A. 1998. Early amyloid deposition in the medial temporal lobe of young down syndrome patients: A regional quantitative analysis. Experimental Neurology 150(2): 296-304.

Lindvall, O. & Kokaia, Z. 2006. Stem cells for the treatment of neurological disorders. Nature 441(7097): 1094-1096.

Llorens-Martin, M.V., Rueda, N., Tejeda, G.S., Florez, J., Trejo, J.L. & Martinez-Cue, C. 2010. Effects of voluntary physical exercise on adult hippocampal neurogenesis and behavior of ts65dn mice, a model of down syndrome. Neuroscience 171(4): 1228-1240.

López-Hidalgo, R., Ballestín, R., Vega1, J., Blasco-Ibáñez, J.M., Crespo, C. & Gilabert-Juan, J. 2016. Hypocellularity in the murine model for down syndrome ts65dn is not affected by adult neurogenesis. Frontiers in Nueroscience 10(75): 1-13.

Lorenzi, H.A. & Reeves, R.H. 2006. Hippocampal hypocellularity in the ts65dn mouse originates early in development. Brain Research 1104(1): 153-159.

Lott, I.T. & Dierssen, M. 2010. Cognitive deficits and associated neurological complications in individuals with down's syndrome. Lancet Neurology 9(6): 623-633.

Lugert, S., Basak, O., Knuckles, P., Haussler, U., Fabel, K. & Gotz, M. 2010. Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging. Cell Stem Cell 6(5): 445-456.

Mccarron, M., Mccallion, P., Reilly, E. & Mulryan, N. 2014. A prospective 14-year longitudinal follow-up of dementia in persons with down syndrome. Journal of Intellectual Disability Research 58(1): 61-70.

Ministry of Health Malaysia. 2015. Guidance Document and Guidelines for Registration of Cell and Gene Therapy Products (CGTPs) In Malaysia. National Down Syndrome Society: About Down Syndrome. https://www.ndss.org/about-down-syndrome/down-syndrome/ Accessed on 15 July 2019.

National Institute of Neurological Disorder & Research. Multiple Sclerosis. 2019. Hope through Research. http://www.ninds.nih.gov/disorders/multiple_sclerosis/detail_multiple_sclerosis.htm.  Accessed on 19 July 2019.

Niles, L.P., Armstrong, K.J., Rinco´n Castro, L.M., Dao, C.V., Sharma, R., McMillan, C.R., Doering, L.C. & Kirkham, D.L. 2004. Neural stem cells express melatonin receptors and neurotrophic factors: Colocalization of the MT1 receptor with neuronal and glial markers. BMC Neuroscience 5: 41-49.

Niu, S., Yabut, O. & D’Arcangelo, G.J. 2008. The reelin signaling pathway promotes dendritic spine development in hippocampal neurons. Journal of Neuroscience 28(41): 10339-10348.

Pallas, M., Camins, A., Smith, M.A., Perry, G., Lee, H.G. & Casadesus, G. 2008. From aging to Alzheimer’s disease: Unveiling “the switch” with the senescence-accelerated mouse model (SAMP8). Journal of Alzheimer’s Disease 15(4): 615-624.

Patil, K.B. 2018. Progenitor Cells vs. Stem Cells: Differences in Roles and Functions. https://biologywise.com/progenitor-cells-vs-stem-cells. Accessed on 20 August 2019.

Pueschel, S.M. & Pueschel, J.K. 1992. Biomedical concerns in persons with down syndrome. Book Reviews 42(12): 222.

Rachubinski, A.L., Crowley, S.K., Sladek, Jr. J.R., Maclean, K.N. & Bjugstad, K.B. 2012a. Effects of neonatal neural progenitor cell implantation on adult neuroanatomy and cognition in the Ts65Dn model of down syndrome. PLoS ONE 7(4): 1-13.

Rachubinski, A.L., Maclean, K.N., Evans, J.R. & Bjugstad, K.B. 2012b. Modulating cognitive deficits and tau accumulation in a mouse model of aging down syndrome through neonatal implantation of neural progenitor cells. Experimental Gerontology 47(9): 723-733.

Reinholdt, L.G., Ding, Y., Gilbert, G.J., Gilbert, G.T., Czechanski, A. & Solzak, J.P. 2011. Molecular characterization of the translocation breakpoints in the down syndrome mouse model Ts65Dn. Mammalian Genome 22(11-12): 685-691.

Roizen, N.J. 2005. Complementary and alternative therapies for Down syndrome. Mental Retardation and Developmental Disabilities Research Reviews 11(2): 149-155.

Roizen, N.J. & Patterson, D. 2003. Down's syndrome. Lancet 361(9365): 1281-1289.

Sebastiá, J., Cristofol, R., Pertusa, M., Vilchez, D., Toran, N. & Barambio, S. 2004. Down's syndrome astrocytes have greater antioxidant capacity than euploid astrocytes. European Journal of Neuroscience 20(9): 2355-2366.

Shen, S., Xia, J. & Wang, J. 2016. Nanomedicine-mediated cancer stem cell therapy. Biomaterials. 74: 1-18.

Shichiri, M., Yoshida, Y., Ishida, N., Hagihara, Y., Iwahashi, H. & Tamai, H. 2011. Alpha-tocopherol suppresses lipid peroxidation and behavioral and cognitive impairments in the ts65dn mouse model of down syndrome. Free Radical Biology and Medicine 50(12): 1801-1811.

Shroff, G. 2016. Human embryonic stem cells in the treatment of patients with down syndrome: A case report. Journal of Medical Cases 7(4): 123-125.

Smith, G.K., Kesner, R.P. & Korenberg, J.R. 2014. Dentate gyrus mediates cognitive function in the Ts65Dn/DnJ mouse model of down syndrome. Hippocampus 24(3): 354-362.

Tomobe, K. & Nomura, Y. 2009. Neurochemistry, neuropathology, and heredity in SAMP8: A mouse model of senescence. Neurochemical Research 34(4): 660-669.

US National Library of Medicine. National Institutes of Health Search database. 2019. https://www.ncbi.nlm.nih.gov/pubmed. Accessed on 19 August 2019.

Van Dyke, D.C., Land, D.J., van Duyne, S., Heide, F. & Chang, H. 1990. Cell therapy in children with down syndrome: A retrospective study. Pediatrics 85(1): 79-84.

Wiseman, F.K., Al-Janabi, T., Hardy, J., Karmiloff-Smith, A., Nizetic, D. & Tybulewicz, V.L. 2015. A genetic cause of Alzheimer disease: Mechanistic insights from down syndrome. Nature Review Neuroscience 16(9): 564-574.

Yang, H., Wen, S.R., Zhang, G.W., Wang, T.G., Hu, F.X. & Li, X.L. 2011. Effects of Chinese herbal medicine Fuzhisan on autologous neural stem cells in the brain of SAMP-8 mice. Experimental Gerontology 46(8): 628-636.

Zigman, W.B., Devenny, D.A., Krinsky-McHale, S.J., Jenkins, E.C., Urv, T.K. & Wegiel, J. 2008. Alzheimer's disease in adults with down syndrome. International Review of Research in Mental Retardation 36: 103-145.

Zis, P. & Strydom, A. 2018. Clinical aspects and biomarkers of Alzheimer’s disease in down syndrome. Free Radical Biology and Medicine 114: 3-9.

*Pengarang untuk surat-menyurat; email: idanasri@ppukm.ukm.edu.my