دورية أكاديمية
Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial.
العنوان: | Transplantation of human neural progenitor cells secreting GDNF into the spinal cord of patients with ALS: a phase 1/2a trial. |
---|---|
المؤلفون: | Baloh RH; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Johnson JP; Cedars-Sinai Spine Center, Los Angeles, CA, USA., Avalos P; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Allred P; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Novartis Institutes for BioMedical Research, Cambridge, MA, USA., Svendsen S; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Gowing G; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Fujifilm Cellular Dynamics, Inc., Madison, WI, USA., Roxas K; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Wu A; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Donahue B; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Osborne S; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Lawless G; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Shelley B; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Fujifilm Cellular Dynamics, Inc., Madison, WI, USA., Wheeler K; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Los Angeles, CA, USA., Prina C; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Fine D; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Kendra-Romito T; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Stokes H; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Manoukian V; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Muthukumaran A; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Garcia L; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Bañuelos MG; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Godoy M; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Department of Psychiatry and Biobehavioral Sciences, UCLA, Los Angeles, CA, USA., Bresee C; Biostatistics Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Yu H; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA., Drazin D; Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Department of Neurosurgery, Providence Regional Medical Center Everett, Everett, WA, USA., Ross L; Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Naruse R; Department of Anesthesiology, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Babu H; Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Department of Neurosurgery, SUNY-Upstate Medical University, Syracuse, NY, USA., Macklin EA; Biostatistics Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA., Vo A; Cedars-Sinai Comprehensive Transplant Center, Los Angeles, CA, USA., Elsayegh A; Department of Pulmonary and Critical Care, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Tourtellotte W; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Maya M; Department of Imaging, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Burford M; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Diaz F; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Patil CG; Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Lewis RA; Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Svendsen CN; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Clive.svendsen@cshs.org. |
المصدر: | Nature medicine [Nat Med] 2022 Sep; Vol. 28 (9), pp. 1813-1822. Date of Electronic Publication: 2022 Sep 05. |
نوع المنشور: | Clinical Trial, Phase I; Clinical Trial, Phase II; Journal Article; Research Support, U.S. Gov't, Non-P.H.S. |
اللغة: | English |
بيانات الدورية: | Publisher: Nature Publishing Company Country of Publication: United States NLM ID: 9502015 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-170X (Electronic) Linking ISSN: 10788956 NLM ISO Abbreviation: Nat Med Subsets: MEDLINE |
أسماء مطبوعة: | Publication: New York Ny : Nature Publishing Company Original Publication: New York, NY : Nature Pub. Co., [1995- |
مواضيع طبية MeSH: | Amyotrophic Lateral Sclerosis*/therapy , Neural Stem Cells*, Animals ; Disease Models, Animal ; Glial Cell Line-Derived Neurotrophic Factor/genetics ; Humans ; Spinal Cord ; Superoxide Dismutase |
مستخلص: | Amyotrophic lateral sclerosis (ALS) involves progressive motor neuron loss, leading to paralysis and death typically within 3-5 years of diagnosis. Dysfunctional astrocytes may contribute to disease and glial cell line-derived neurotrophic factor (GDNF) can be protective. Here we show that human neural progenitor cells transduced with GDNF (CNS10-NPC-GDNF) differentiated to astrocytes protected spinal motor neurons and were safe in animal models. CNS10-NPC-GDNF were transplanted unilaterally into the lumbar spinal cord of 18 ALS participants in a phase 1/2a study (NCT02943850). The primary endpoint of safety at 1 year was met, with no negative effect of the transplant on motor function in the treated leg compared with the untreated leg. Tissue analysis of 13 participants who died of disease progression showed graft survival and GDNF production. Benign neuromas near delivery sites were common incidental findings at post-mortem. This study shows that one administration of engineered neural progenitors can provide new support cells and GDNF delivery to the ALS patient spinal cord for up to 42 months post-transplantation. (© 2022. The Author(s).) |
التعليقات: | Comment in: Nat Med. 2022 Sep;28(9):1751-1752. (PMID: 36097225) Comment in: Trends Mol Med. 2022 Nov;28(11):897-899. (PMID: 36182630) |
References: | Jaiswal, M. K. Riluzole and edaravone: a tale of two amyotrophic lateral sclerosis drugs. Med. Res. Rev. 39, 733–748 (2019). (PMID: 3010149610.1002/med.21528) Harms, M. B. & Baloh, R. H. Clinical neurogenetics: amyotrophic lateral sclerosis. Neurol. Clin. 31, 929–950 (2013). (PMID: 2417641710.1016/j.ncl.2013.05.003) Mueller, C. et al. SOD1 suppression with adeno-associated virus and microRNA in familial ALS. N. Engl. J. Med. 383, 151–158 (2020). (PMID: 3264013310.1056/NEJMoa2005056) Miller, T. et al. Phase 1–2 trial of antisense oligonucleotide tofersen for SOD1 ALS. N. Engl. J. Med. 383, 109–119 (2020). (PMID: 3264013010.1056/NEJMoa2003715) Du, Z.-W. et al. Generation and expansion of highly pure motor neuron progenitors from human pluripotent stem cells. Nat. Commun. 6, 6626 (2015). (PMID: 2580642710.1038/ncomms7626) Baloh, R. H., Glass, J. D. & Svendsen, C. N. Stem cell transplantation for amyotrophic lateral sclerosis. Curr. Opin. Neurol. 31, 655–661 (2018). (PMID: 3008071910.1097/WCO.0000000000000598) Mazzini, L. et al. Mesenchymal stem cell transplantation in amyotrophic lateral sclerosis: a phase I clinical trial. Exp. Neurol. 223, 229–237 (2010). (PMID: 1968298910.1016/j.expneurol.2009.08.007) Berry, J. D. et al. NurOwn, phase 2, randomized, clinical trial in patients with ALS: safety, clinical, and biomarker results. Neurology 93, e2294–e2305 (2019). (PMID: 31740545693749710.1212/WNL.0000000000008620) Mazzini, L. et al. Results from phase I clinical trial with intraspinal injection of neural stem cells in amyotrophic lateral sclerosis: a long-term outcome. Stem Cells Transl. Med. 8, 887–897 (2019). (PMID: 31104357670807010.1002/sctm.18-0154) Glass, J. D. et al. Transplantation of spinal cord-derived neural stem cells for ALS: analysis of phase 1 and 2 trials. Neurology 87, 392–400 (2016). (PMID: 27358335497711610.1212/WNL.0000000000002889) Goutman, S. A. et al. Long-term phase 1/2 intraspinal stem cell transplantation outcomes in ALS. Ann. Clin. Transl. Neurol. 5, 730–740 (2018). (PMID: 29928656598973610.1002/acn3.567) Bruijn, L. I. et al. ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18, 327–338 (1997). (PMID: 905280210.1016/S0896-6273(00)80272-X) Clement, A. M. et al. Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302, 113–117 (2003). (PMID: 1452608310.1126/science.1086071) Lepore, A. C. et al. Focal transplantation-based astrocyte replacement is neuroprotective in a model of motor neuron disease. Nat. Neurosci. 11, 1294–1301 (2008). (PMID: 18931666265668610.1038/nn.2210) Svendsen, C. N. et al. Long-term survival of human central nervous system progenitor cells transplanted into a rat model of Parkinson’s disease. Exp. Neurol. 148, 135–146 (1997). (PMID: 939845610.1006/exnr.1997.6634) Klein, S. M. et al. GDNF delivery using human neural progenitor cells in a rat model of ALS. Hum. Gene Ther. 16, 509–521 (2005). (PMID: 1587168210.1089/hum.2005.16.509) Behrstock, S. et al. Human neural progenitors deliver glial cell line-derived neurotrophic factor to parkinsonian rodents and aged primates. Gene Ther. 13, 379–388 (2006). (PMID: 1635511610.1038/sj.gt.3302679) McBride, J. L. et al. Human neural stem cell transplants improve motor function in a rat model of Huntington’s disease. J. Comp. Neurol. 475, 211–219 (2004). (PMID: 1521146210.1002/cne.20176) Behrstock, S. et al. Lesion-induced increase in survival and migration of human neural progenitor cells releasing GDNF. Cell Transplant. 17, 753–762 (2008). (PMID: 1904420210.3727/096368908786516819) Ostenfeld, T. et al. Human neural precursor cells express low levels of telomerase in vitro and show diminishing cell proliferation with extensive axonal outgrowth following transplantation. Exp. Neurol. 164, 215–226 (2000). (PMID: 1087793210.1006/exnr.2000.7427) Andres, R. H. et al. Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain. Brain 134, 1777–1789 (2011). (PMID: 21616972310224310.1093/brain/awr094) Gutierrez, J. et al. Preclinical validation of multilevel intraparenchymal stem cell therapy in the porcine spinal cord. Neurosurgery 77, 604–612 (2015); discussion 612. (PMID: 2613459610.1227/NEU.0000000000000882) Emborg, M. E. et al. GDNF-secreting human neural progenitor cells increase tyrosine hydroxylase and VMAT2 expression in MPTP-treated cynomolgus monkeys. Cell Transplant. 17, 383–395 (2008). (PMID: 1852224110.3727/096368908784423300) Wang, S. et al. Long-term vision rescue by human neural progenitors in a rat model of photoreceptor degeneration. Invest. Ophthalmol. Vis. Sci. 49, 3201–3206 (2008). (PMID: 1857976510.1167/iovs.08-1831) Suzuki, M. et al. GDNF secreting human neural progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of familial ALS. PLoS ONE 2, e689 (2007). (PMID: 17668067192515010.1371/journal.pone.0000689) Gowing, G. et al. Glial cell line-derived neurotrophic factor-secreting human neural progenitors show long-term survival, maturation into astrocytes, and no tumor formation following transplantation into the spinal cord of immunocompromised rats. Neuroreport 25, 367–372 (2014). (PMID: 24284956396915410.1097/WNR.0000000000000092) Das, M. M. et al. Human neural progenitors differentiate into astrocytes and protect motor neurons in aging rats. Exp. Neurol. 280, 41–49 (2016). (PMID: 2703272110.1016/j.expneurol.2016.03.023) Thomsen, G. M. et al. Transplantation of neural progenitor cells expressing glial cell line-derived neurotrophic factor into the motor cortex as a strategy to treat amyotrophic lateral sclerosis. Stem Cells 36, 1122–1131 (2018). (PMID: 2965647810.1002/stem.2825) Lepore, A. C. et al. Human glial-restricted progenitor transplantation into cervical spinal cord of the SOD1 mouse model of ALS. PLoS ONE 6, e25968 (2011). (PMID: 21998733318782910.1371/journal.pone.0025968) Lin, L. F., Doherty, D. H., Lile, J. D., Bektesh, S. & Collins, F. GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260, 1130–1132 (1993). (PMID: 849355710.1126/science.8493557) Henderson, C. E. et al. GDNF: a potent survival factor for motoneurons present in peripheral nerve and muscle. Science 266, 1062–1064 (1994). (PMID: 797366410.1126/science.7973664) Gill, S. S. et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat. Med. 9, 589–595 (2003). (PMID: 1266903310.1038/nm850) Slevin, J. T. et al. Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell line-derived neurotrophic factor. J. Neurosurg. 102, 216–222 (2005). (PMID: 1573954710.3171/jns.2005.102.2.0216) Alisky, J. M. & Davidson, B. L. Gene therapy for amyotrophic lateral sclerosis and other motor neuron diseases. Hum. Gene Ther. 11, 2315–2329 (2000). (PMID: 1109643710.1089/104303400750038435) Shelley, B. C., Gowing, G. & Svendsen, C. N. A cGMP-applicable expansion method for aggregates of human neural stem and progenitor cells derived from pluripotent stem cells or fetal brain tissue. J. Vis. Exp. 88, 51219 (2014); https://doi.org/10.3791/51219. Hovland, D. N. et al. Six-month continuous intraputamenal infusion toxicity study of recombinant methionyl human glial cell line-derived neurotrophic factor (r-metHuGDNF) in rhesus monkeys. Toxicol. Pathol. 35, 676–692 (2007). (PMID: 1776328210.1177/01926230701481899a) Winkler, J. et al. Reversible Schwann cell hyperplasia and sprouting of sensory and sympathetic neurites after intraventricular administration of nerve growth factor. Ann. Neurol. 41, 82–93 (1997). (PMID: 900586910.1002/ana.410410114) Day-Lollini, P. A., Stewart, G. R., Taylor, M. J., Johnson, R. M. & Chellman, G. J. Hyperplastic changes within the leptomeninges of the rat and monkey in response to chronic intracerebroventricular infusion of nerve growth factor. Exp. Neurol. 145, 24–37 (1997). (PMID: 918410610.1006/exnr.1997.6448) Rushton, D. J., Andres, P. L., Allred, P., Baloh, R. H. & Svendsen, C. N. Patients with ALS show highly correlated progression rates in left and right limb muscles. Neurology 89, 196–206 (2017). (PMID: 28600459550193510.1212/WNL.0000000000004105) Pradas, J. et al. The natural history of amyotrophic lateral sclerosis and the use of natural history controls in therapeutic trials. Neurology 43, 751–755 (1993). (PMID: 846933510.1212/WNL.43.4.751) Thomsen, G. M. et al. Systemic injection of AAV9-GDNF provides modest functional improvements in the SOD1G93A ALS rat but has adverse side effects. Gene Ther. 24, 245–252 (2017). (PMID: 28276446540420610.1038/gt.2017.9) Thomas Cheng, H. Spinal cord mechanisms of chronic pain and clinical implications. Curr. Pain. Headache Rep. 14, 213–220 (2010). (PMID: 2046147610.1007/s11916-010-0111-0) Mendez, I. et al. Cell type analysis of functional fetal dopamine cell suspension transplants in the striatum and substantia nigra of patients with Parkinson’s disease. Brain 128, 1498–1510 (2005). (PMID: 1587202010.1093/brain/awh510) Hauser, R. A. et al. Long-term evaluation of bilateral fetal nigral transplantation in Parkinson disease. Arch. Neurol. 56, 179–187 (1999). (PMID: 1002542310.1001/archneur.56.2.179) Kordower, J. H. et al. Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson’s disease. N. Engl. J. Med. 332, 1118–1124 (1995). (PMID: 770028410.1056/NEJM199504273321702) Kordower, J. H. et al. Fetal grafting for Parkinson’s disease: expression of immune markers in two patients with functional fetal nigral implants. Cell Transplant. 6, 213–219 (1997). (PMID: 917115410.1177/096368979700600304) Xu, P. et al. Nerve injury induces glial cell line-derived neurotrophic factor (GDNF) expression in Schwann cells through purinergic signaling and the PKC-PKD pathway. Glia 61, 1029–1040 (2013). (PMID: 23553603416561210.1002/glia.22491) Reith, W. & Haußmann, A. Importance of Virchow–Robin spaces. Radiologie 58, 142–147 (2018). (PMID: 10.1007/s00117-017-0354-4) Imitola, J. et al. Directed migration of neural stem cells to sites of CNS injury by the stromal cell-derived factor 1alpha/CXC chemokine receptor 4 pathway. Proc. Natl Acad. Sci. USA 101, 18117–18122 (2004). (PMID: 1560806253605510.1073/pnas.0408258102) Nichols, N. L. et al. Intermittent hypoxia and stem cell implants preserve breathing capacity in a rodent model of amyotrophic lateral sclerosis. Am. J. Respir. Crit. Care Med. 187, 535–542 (2013). (PMID: 23220913373340910.1164/rccm.201206-1072OC) Svendsen, C. N. et al. A new method for the rapid and long term growth of human neural precursor cells. J. Neurosci. Methods 85, 141–152 (1998). (PMID: 987415010.1016/S0165-0270(98)00126-5) Andres, P. L. et al. Validation of a new strength measurement device for amyotrophic lateral sclerosis clinical trials. Muscle Nerve 45, 81–85 (2012). (PMID: 2219031210.1002/mus.22253) Andres, P. L. et al. Fixed dynamometry is more sensitive than vital capacity or ALS rating scale. Muscle Nerve 56, 710–715 (2017). (PMID: 2812041310.1002/mus.25586) Liang, K.-Y. & Zeger, S. L. Longitudinal data analysis of continuous and discrete responses for pre–post designs. Sankhyā Ind. J. Stat. Ser. B (1960–2002) 62, 134–148 (2000). |
معلومات مُعتمدة: | K26 OD010945 United States OD NIH HHS; K26 RR026099 United States RR NCRR NIH HHS; R01 NS095894 United States NS NINDS NIH HHS |
سلسلة جزيئية: | ClinicalTrials.gov NCT02943850 |
المشرفين على المادة: | 0 (Glial Cell Line-Derived Neurotrophic Factor) EC 1.15.1.1 (Superoxide Dismutase) |
تواريخ الأحداث: | Date Created: 20220905 Date Completed: 20220926 Latest Revision: 20221130 |
رمز التحديث: | 20221213 |
مُعرف محوري في PubMed: | PMC9499868 |
DOI: | 10.1038/s41591-022-01956-3 |
PMID: | 36064599 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1546-170X |
---|---|
DOI: | 10.1038/s41591-022-01956-3 |