Future Advances in Early Phase Clinical Development for Disease Modifying Therapies for Neurodegenerative Diseases
Main Article Content
Abstract
With aging populations in many countries, the prevalence of neurodegenerative diseases is expected to increase in the upcoming decades. Currently, no disease modifying therapies for these conditions exist. Advances in genetics and proteomics have identified novel druggable targets for neurodegenerative diseases. Compounds modulating these targets have recently entered clinical trials. These compounds can be orally administered small drug molecules, intravenously dosed antibodies, intrathecally injected antisense oligonucleotides (ASOs), gene therapies, stem cells or viral vectors. For the development of these compounds to be successful, multiple challenges have to be overcome. In this review we discuss advances in drug development for each of the major neurodegenerative diseases, which, when applied to early phase drug studies, increase the chance of successful clinical development. Here we will limit ourselves to: 1) the use of biomarkers for understanding target and pathway engagement at an early stage of development, 2) novel approaches for increasing blood-brain barrier penetration and 3) advances in understanding cerebrospinal fluid flow dynamics in relation to neurodegeneration and target site distribution for intrathecally administered compounds.
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How to Cite
KREMER, Philip H.C.; GROENEVELD, Geert Jan.
Future Advances in Early Phase Clinical Development for Disease Modifying Therapies for Neurodegenerative Diseases.
Medical Research Archives, [S.l.], v. 10, n. 9, sep. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3042>. Date accessed: 05 nov. 2024.
doi: https://doi.org/10.18103/mra.v10i9.3042.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. GBD 2016 Neurology Collaborators. Global, regional, and national burden of neurological disorders, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18(5):459-480.
2. Cummings J, Fox N. Defining Disease Modifying Therapy for Alzheimer’s Disease. J Prev Alzheimers Dis. 2017;4(2):109-115.
3. Plascencia-Villa G, Perry G. Status and future directions of clinical trials in Alzheimer’s disease. Int Rev Neurobiol. 2020;154:3-50.
4. McFarthing K, Buff S, Rafaloff G, Dominey T, Wyse RK, Stott SRW. Parkinson’s Disease Drug Therapies in the Clinical Trial Pipeline: 2020. J Parkinsons Dis. 2020;10(3):757-774.
5. Bonam SR, Wang F, Muller S. Lysosomes as a therapeutic target. Nat Rev Drug Discov. 2019;18(12):923-948.
6. Levine B, Deretic V. Unveiling the roles of autophagy in innate and adaptive immunity. Nat Rev Immunol. 2007;7(10):767-777.
7. Deus CM, Yambire KF, Oliveira PJ, Raimundo N. Mitochondria-Lysosome Crosstalk: From Physiology to Neurodegeneration. Trends Mol Med. 2020;26(1):71-88.
8. Cooper AA, Gitler AD, Cashikar A, et al. Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science. 2006;313(5785):324-328.
9. Gitler AD, Bevis BJ, Shorter J, et al. The Parkinson’s disease protein alpha-synuclein disrupts cellular Rab homeostasis. Proc Natl Acad Sci U S A. 2008;105(1):145-150.
10. Tardiff DF, Jui NT, Khurana V, et al. Yeast reveal a “druggable” Rsp5/Nedd4 network that ameliorates α-synuclein toxicity in neurons. Science. 2013;342(6161):979-983.
11. Eguchi T, Kuwahara T, Sakurai M, et al. LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis. Proc Natl Acad Sci U S A. 2018;115(39):E9115-E9124.
12. Purlyte E, Dhekne HS, Sarhan AR, et al. Rab29 activation of the Parkinson’s disease-associated LRRK2 kinase. EMBO J. 2019;38(2). doi:10.15252/embj.2018101237
13. Steger M, Tonelli F, Ito G, et al. Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. Elife. 2016;5. doi:10.7554/eLife.12813
14. Henderson MX, Sedor S, McGeary I, et al. Glucocerebrosidase Activity Modulates Neuronal Susceptibility to Pathological α-Synuclein Insult. Neuron. 2020;105(5):822-836.e7.
15. Pierce S, Coetzee GA. Parkinson’s disease-associated genetic variation is linked to quantitative expression of inflammatory genes. PLoS One. 2017;12(4):e0175882.
16. Caggiu E, Arru G, Hosseini S, et al. Inflammation, Infectious Triggers, and Parkinson’s Disease. Front Neurol. 2019;10:122.
17. Chang D, Nalls MA, Hallgrímsdóttir IB, et al. A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat Genet. 2017;49(10):1511-1516.
18. Karch CM, Goate AM. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry. 2015;77(1):43-51.
19. Lambert JC, Ibrahim-Verbaas CA, Harold D, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 2013;45(12):1452-1458.
20. Jonsson T, Stefansson H, Steinberg S, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med. 2013;368(2):107-116.
21. Keren-Shaul H, Spinrad A, Weiner A, et al. A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell. 2017;169(7):1276-1290.e17.
22. Krasemann S, Madore C, Cialic R, et al. The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity. 2017;47(3):566-581.e9.
23. Katsouri L, Lim YM, Blondrath K, et al. PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model. Proc Natl Acad Sci U S A. 2016;113(43):12292-12297.
24. Ramesh N, Pandey UB. Autophagy Dysregulation in ALS: When Protein Aggregates Get Out of Hand. Front Mol Neurosci. 2017;10:263.
25. Renton AE, Chiò A, Traynor BJ. State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci. 2014;17(1):17-23.
26. Turner MR, Cagnin A, Turkheimer FE, et al. Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis. 2004;15(3):601-609.
27. Henkel JS, Engelhardt JI, Siklós L, et al. Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann Neurol. 2004;55(2):221-235.
28. Lall D, Baloh RH. Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia. J Clin Invest. 2017;127(9):3250-3258.
29. Vissers MFJM, Heuberger JAAC, Groeneveld GJ. Targeting for Success: Demonstrating Proof-of-Concept with Mechanistic Early Phase Clinical Pharmacology Studies for Disease-Modification in Neurodegenerative Disorders. Int J Mol Sci. 2021;22(4). doi:10.3390/ijms22041615
30. Beach TG. A Review of Biomarkers for Neurodegenerative Disease: Will They Swing Us Across the Valley? Neurol Ther. 2017;6(Suppl 1):5-13.
31. Cohen AF, Burggraaf J, van Gerven JMA, Moerland M, Groeneveld GJ. The use of biomarkers in human pharmacology (Phase I) studies. Annu Rev Pharmacol Toxicol. 2015;55:55-74.
32. Tardiff DF, Lucas M, Wrona I, et al. Non-clinical Pharmacology of YTX-7739: a Clinical Stage Stearoyl-CoA Desaturase Inhibitor Being Developed for Parkinson’s Disease. Mol Neurobiol. 2022;59(4):2171-2189.
33. Nuber S, Chung CY, Tardiff DF, et al. A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity. Neurotherapeutics. Published online April 20, 2022. doi:10.1007/s13311-022-01199-7
34. den Heijer JM, Kruithof AC, van Amerongen G, et al. A randomized single and multiple ascending dose study in healthy volunteers of LTI-291, a centrally penetrant glucocerebrosidase activator. Br J Clin Pharmacol. 2021;87(9):3561-3573.
35. Jennings D, Huntwork-Rodriguez S, Henry AG, et al. Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson’s disease. Sci Transl Med. 2022;14(648):eabj2658.
36. Monnet E, Lapeyre G, van Poelgeest E, et al. Evidence of NI-0101 pharmacological activity, an anti-TLR4 antibody, in a randomized phase I dose escalation study in healthy volunteers receiving LPS. Clin Pharmacol Ther. 2017;101(2):200-208.
37. Grievink HW, Jirka SMG, Woutman TD, et al. Antimicrobial Peptide Omiganan Enhances Interferon Responses to Endosomal Toll-Like Receptor Ligands in Human Peripheral Blood Mononuclear Cells. Clin Transl Sci. 2020;13(5):891-895.
38. Vissers MFJM, Heuberger JAAC, Groeneveld GJ, et al. Safety, pharmacokinetics and target engagement of novel RIPK1 inhibitor SAR443060 (DNL747) for neurodegenerative disorders: Randomized, placebo-controlled, double-blind phase I/Ib studies in healthy subjects and patients. Clin Transl Sci. Published online June 1, 2022. doi:10.1111/cts.13317
39. Cai X, Xu Y, Cheung AK, et al. PIKfyve, a class III PI kinase, is the target of the small molecular IL-12/IL-23 inhibitor apilimod and a player in Toll-like receptor signaling. Chem Biol. 2013;20(7):912-921.
40. Khasawneh AH, Garling RJ, Harris CA. Cerebrospinal fluid circulation: What do we know and how do we know it? Brain Circ. 2018;4(1):14-18.
41. Bulat M, Klarica M. Recent insights into a new hydrodynamics of the cerebrospinal fluid. Brain Res Rev. 2011;65(2):99-112.
42. Johanson C, Johanson N. Merging Transport Data for Choroid Plexus with Blood-Brain Barrier to Model CNS Homeostasis and Disease More Effectively. CNS Neurol Disord Drug Targets. 2016;15(9):1151-1180.
43. Sakka L, Coll G, Chazal J. Anatomy and physiology of cerebrospinal fluid. Eur Ann Otorhinolaryngol Head Neck Dis. 2011;128(6):309-316.
44. Green KN, Crapser JD, Hohsfield LA. To Kill a Microglia: A Case for CSF1R Inhibitors. Trends Immunol. 2020;41(9):771-784.
45. Khalil M, Teunissen CE, Otto M, et al. Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol. 2018;14(10):577-589.
46. Byeon SK, Madugundu AK, Jain AP, et al. Cerebrospinal fluid lipidomics for biomarkers of Alzheimer’s disease. Mol Omics. 2021;17(3):454-463.
47. Bader JM, Geyer PE, Müller JB, et al. Proteome profiling in cerebrospinal fluid reveals novel biomarkers of Alzheimer’s disease. Mol Syst Biol. 2020;16(6):e9356.
48. Sokoloff L. Energetics of functional activation in neural tissues. Neurochem Res. 1999;24(2):321-329.
49. Kleinberger G, Brendel M, Mracsko E, et al. The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. EMBO J. 2017;36(13):1837-1853.
50. Xiang X, Wind K, Wiedemann T, et al. Microglial activation states drive glucose uptake and FDG-PET alterations in neurodegenerative diseases. Sci Transl Med. 2021;13(615):eabe5640.
51. Budd Haeberlein S, Aisen PS, Barkhof F, et al. Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease. J Prev Alzheimers Dis. 2022;9(2):197-210.
52. Mintun MA, Lo AC, Duggan Evans C, et al. Donanemab in Early Alzheimer’s Disease. N Engl J Med. 2021;384(18):1691-1704.
53. Honig LS, Vellas B, Woodward M, et al. Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease. N Engl J Med. 2018;378(4):321-330.
54. Smart K, Naganawa M, Baldassarri SR, et al. PET Imaging Estimates of Regional Acetylcholine Concentration Variation in Living Human Brain. Cereb Cortex. 2021;31(6):2787-2798.
55. Kim YJ, Ichise M, Ballinger JR, et al. Combination of dopamine transporter and D2 receptor SPECT in the diagnostic evaluation of PD, MSA, and PSP. Mov Disord. 2002;17(2):303-312.
56. Hadoux X, Hui F, Lim JKH, et al. Non-invasive in vivo hyperspectral imaging of the retina for potential biomarker use in Alzheimer’s disease. Nat Commun. 2019;10(1):4227.
57. Mochel F, N’Guyen TM, Deelchand D, et al. Abnormal response to cortical activation in early stages of Huntington disease. Mov Disord. 2012;27(7):907-910.
58. Adanyeguh IM, Rinaldi D, Henry PG, et al. Triheptanoin improves brain energy metabolism in patients with Huntington disease. Neurology. 2015;84(5):490-495.
59. van Diemen MPJ, Hart EP, Abbruscato A, et al. Safety, pharmacokinetics and pharmacodynamics of SBT-020 in patients with early stage Huntington’s disease, a 2-part study. Br J Clin Pharmacol. 2021;87(5):2290-2302.
60. Bouldin TW, Krigman MR. Differential permeability of cerebral capillary and choroid plexus to lanthanum ion. Brain Res. 1975;99(2):444-448.
61. Ferguson RK, Woodbury DM. Penetration of 14C-inulin and 14C-sucrose into brain, cerebrospinal fluid, and skeletal muscle of developing rats. Exp Brain Res. 1969;7(3):181-194.
62. Pardridge WM. Blood-Brain Barrier and Delivery of Protein and Gene Therapeutics to Brain. Front Aging Neurosci. 2019;11:373.
63. Reiber H. Proteins in cerebrospinal fluid and blood: barriers, CSF flow rate and source-related dynamics. Restor Neurol Neurosci. 2003;21(3-4):79-96.
64. Boado RJ, Zhang Y, Zhang Y, Xia CF, Pardridge WM. Fusion antibody for Alzheimer’s disease with bidirectional transport across the blood-brain barrier and abeta fibril disaggregation. Bioconjug Chem. 2007;18(2):447-455.
65. Pardridge WM. Blood-brain barrier endogenous transporters as therapeutic targets: a new model for small molecule CNS drug discovery. Expert Opin Ther Targets. 2015;19(8):1059-1072.
66. Banks WA. The source of cerebral insulin. Eur J Pharmacol. 2004;490(1-3):5-12.
67. Pardridge WM, Eisenberg J, Yang J. Human blood-brain barrier transferrin receptor. Metabolism. 1987;36(9):892-895.
68. Reinhardt RR, Bondy CA. Insulin-like growth factors cross the blood-brain barrier. Endocrinology. 1994;135(5):1753-1761.
69. Demeule M, Currie JC, Bertrand Y, et al. Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector angiopep-2. J Neurochem. 2008;106(4):1534-1544.
70. Golden PL, Maccagnan TJ, Pardridge WM. Human blood-brain barrier leptin receptor. Binding and endocytosis in isolated human brain microvessels. J Clin Invest. 1997;99(1):14-18.
71. Schlachetzki F, Zhu C, Pardridge WM. Expression of the neonatal Fc receptor (FcRn) at the blood-brain barrier. J Neurochem. 2002;81(1):203-206.
72. Boado RJ, Ka-Wai Hui E, Zhiqiang Lu J, Pardridge WM. Insulin receptor antibody-iduronate 2-sulfatase fusion protein: pharmacokinetics, anti-drug antibody, and safety pharmacology in Rhesus monkeys. Biotechnol Bioeng. 2014;111(11):2317-2325.
73. Sonoda H, Morimoto H, Yoden E, et al. A Blood-Brain-Barrier-Penetrating Anti-human Transferrin Receptor Antibody Fusion Protein for Neuronopathic Mucopolysaccharidosis II. Mol Ther. 2018;26(5):1366-1374.
74. Morimoto H, Kida S, Yoden E, et al. Clearance of heparan sulfate in the brain prevents neurodegeneration and neurocognitive impairment in MPS II mice. Mol Ther. 2021;29(5):1853-1861.
75. Giugliani R, Martins AM, So S, et al. Iduronate-2-sulfatase fused with anti-hTfR antibody, pabinafusp alfa, for MPS-II: A phase 2 trial in Brazil. Mol Ther. 2021;29(7):2378-2386.
76. Okuyama T, Eto Y, Sakai N, et al. A Phase 2/3 Trial of Pabinafusp Alfa, IDS Fused with Anti-Human Transferrin Receptor Antibody, Targeting Neurodegeneration in MPS-II. Mol Ther. 2021;29(2):671-679.
77. Ullman JC, Arguello A, Getz JA, et al. Brain delivery and activity of a lysosomal enzyme using a blood-brain barrier transport vehicle in mice. Sci Transl Med. 2020;12(545). doi:10.1126/scitranslmed.aay1163
78. Arguello A, Mahon CS, Calvert MEK, et al. Molecular architecture determines brain delivery of a transferrin receptor-targeted lysosomal enzyme. J Exp Med. 2022;219(3). doi:10.1084/jem.20211057
79. Zhou X, Smith QR, Liu X. Brain penetrating peptides and peptide-drug conjugates to overcome the blood-brain barrier and target CNS diseases. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2021;13(4):e1695.
80. Kurzrock R, Gabrail N, Chandhasin C, et al. Safety, pharmacokinetics, and activity of GRN1005, a novel conjugate of angiopep-2, a peptide facilitating brain penetration, and paclitaxel, in patients with advanced solid tumors. Mol Cancer Ther. 2012;11(2):308-316.
81. Drappatz J, Brenner A, Wong ET, et al. Phase I study of GRN1005 in recurrent malignant glioma. Clin Cancer Res. 2013;19(6):1567-1576.
82. Kariolis MS, Wells RC, Getz JA, et al. Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys. Sci Transl Med. 2020;12(545). doi:10.1126/scitranslmed.aay1359
83. Yin Y, Wang J, Yang M, et al. Penetration of the blood-brain barrier and the anti-tumour effect of a novel PLGA-lysoGM1/DOX micelle drug delivery system. Nanoscale. 2020;12(5):2946-2960.
84. Burks SR, Kersch CN, Witko JA, et al. Blood-brain barrier opening by intracarotid artery hyperosmolar mannitol induces sterile inflammatory and innate immune responses. Proc Natl Acad Sci U S A. 2021;118(18). doi:10.1073/pnas.2021915118
85. Bartus RT, Elliott PJ, Dean RL, et al. Controlled modulation of BBB permeability using the bradykinin agonist, RMP-7. Exp Neurol. 1996;142(1):14-28.
86. Parrish KE, Sarkaria JN, Elmquist WF. Improving drug delivery to primary and metastatic brain tumors: strategies to overcome the blood-brain barrier. Clin Pharmacol Ther. 2015;97(4):336-346.
87. Niu J, Xie J, Guo K, et al. Efficient treatment of Parkinson’s disease using ultrasonography-guided rhFGF20 proteoliposomes. Drug Deliv. 2018;25(1):1560-1569.
88. Lipsman N, Meng Y, Bethune AJ, et al. Blood-brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. Nat Commun. 2018;9(1):2336.
89. Gasca-Salas C, Fernández-Rodríguez B, Pineda-Pardo JA, et al. Blood-brain barrier opening with focused ultrasound in Parkinson’s disease dementia. Nat Commun. 2021;12(1):779.
90. Salahuddin TS, Johansson BB, Kalimo H, Olsson Y. Structural changes in the rat brain after carotid infusions of hyperosmolar solutions. An electron microscopic study. Acta Neuropathol. 1988;77(1):5-13.
91. Rautio J, Kumpulainen H, Heimbach T, et al. Prodrugs: design and clinical applications. Nat Rev Drug Discov. 2008;7(3):255-270.
92. Bakker C, van der Aart J, Hart EP, et al. Safety, pharmacokinetics, and pharmacodynamics of Gln-1062, a prodrug of galantamine. Alzheimers Dement. 2020;6(1):e12093.
93. Hey JA, Yu JY, Versavel M, et al. Clinical Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimer’s Disease. Clin Pharmacokinet. 2018;57(3):315-333.
94. Hartley MD, Shokat MD, DeBell MJ, Banerji T, Kirkemo LL, Scanlan TS. Pharmacological Complementation Remedies an Inborn Error of Lipid Metabolism. Cell Chem Biol. 2020;27(5):551-559.e4.
95. Lang AE, Gill S, Patel NK, et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol. 2006;59(3):459-466.
96. Salvatore MF, Ai Y, Fischer B, et al. Point source concentration of GDNF may explain failure of phase II clinical trial. Exp Neurol. 2006;202(2):497-505.
97. Whone A, Luz M, Boca M, et al. Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson’s disease. Brain. 2019;142(3):512-525.
98. Yadav DB, Maloney JA, Wildsmith KR, et al. Widespread brain distribution and activity following i.c.v. infusion of anti-β-secretase (BACE1) in nonhuman primates. Br J Pharmacol. 2017;174(22):4173-4185.
99. Ziegler RJ, Salegio EA, Dodge JC, et al. Distribution of acid sphingomyelinase in rodent and non-human primate brain after intracerebroventricular infusion. Exp Neurol. 2011;231(2):261-271.
100. Berg SL, Chamberlain MC. Systemic chemotherapy, intrathecal chemotherapy, and symptom management in the treatment of leptomeningeal metastasis. Curr Oncol Rep. 2003;5(1):29-40.
101. Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017;377(18):1723-1732.
102. Mercuri E, Darras BT, Chiriboga CA, et al. Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. N Engl J Med. 2018;378(7):625-635.
103. Chen Y, Liu L. Modern methods for delivery of drugs across the blood-brain barrier. Adv Drug Deliv Rev. 2012;64(7):640-665.
104. Zhang ET, Inman CB, Weller RO. Interrelationships of the pia mater and the perivascular (Virchow-Robin) spaces in the human cerebrum. J Anat. 1990;170:111-123.
105. Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012;4(147):147ra111.
106. Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14(3):133-150.
107. Sallerin-Caute B, Lazorthes Y, Monsarrat B, Cros J, Bastide R. CSF baclofen levels after intrathecal administration in severe spasticity. Eur J Clin Pharmacol. 1991;40(4):363-365.
108. Shafer SL, Eisenach JC, Hood DD, Tong C. Cerebrospinal fluid pharmacokinetics and pharmacodynamics of intrathecal neostigmine methylsulfate in humans. Anesthesiology. 1998;89(5):1074-1088.
109. Wolf DA, Hesterman JY, Sullivan JM, et al. Dynamic dual-isotope molecular imaging elucidates principles for optimizing intrathecal drug delivery. JCI Insight. 2016;1(2):e85311.
110. Papisov MI, Belov VV, Gannon KS. Physiology of the intrathecal bolus: the leptomeningeal route for macromolecule and particle delivery to CNS. Mol Pharm. 2013;10(5):1522-1532.
111. Verma A, Hesterman JY, Chazen JL, et al. Intrathecal 99mTc-DTPA imaging of molecular passage from lumbar cerebrospinal fluid to brain and periphery in humans. Alzheimers Dement. 2020;12(1):e12030.
112. Khani M, Burla GKR, Sass LR, et al. Human in silico trials for parametric computational fluid dynamics investigation of cerebrospinal fluid drug delivery: impact of injection location, injection protocol, and physiology. Fluids Barriers CNS. 2022;19(1):8.
113. Sullivan JM, Mazur C, Wolf DA, et al. Convective forces increase rostral delivery of intrathecal radiotracers and antisense oligonucleotides in the cynomolgus monkey nervous system. J Transl Med. 2020;18(1):309.
2. Cummings J, Fox N. Defining Disease Modifying Therapy for Alzheimer’s Disease. J Prev Alzheimers Dis. 2017;4(2):109-115.
3. Plascencia-Villa G, Perry G. Status and future directions of clinical trials in Alzheimer’s disease. Int Rev Neurobiol. 2020;154:3-50.
4. McFarthing K, Buff S, Rafaloff G, Dominey T, Wyse RK, Stott SRW. Parkinson’s Disease Drug Therapies in the Clinical Trial Pipeline: 2020. J Parkinsons Dis. 2020;10(3):757-774.
5. Bonam SR, Wang F, Muller S. Lysosomes as a therapeutic target. Nat Rev Drug Discov. 2019;18(12):923-948.
6. Levine B, Deretic V. Unveiling the roles of autophagy in innate and adaptive immunity. Nat Rev Immunol. 2007;7(10):767-777.
7. Deus CM, Yambire KF, Oliveira PJ, Raimundo N. Mitochondria-Lysosome Crosstalk: From Physiology to Neurodegeneration. Trends Mol Med. 2020;26(1):71-88.
8. Cooper AA, Gitler AD, Cashikar A, et al. Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson’s models. Science. 2006;313(5785):324-328.
9. Gitler AD, Bevis BJ, Shorter J, et al. The Parkinson’s disease protein alpha-synuclein disrupts cellular Rab homeostasis. Proc Natl Acad Sci U S A. 2008;105(1):145-150.
10. Tardiff DF, Jui NT, Khurana V, et al. Yeast reveal a “druggable” Rsp5/Nedd4 network that ameliorates α-synuclein toxicity in neurons. Science. 2013;342(6161):979-983.
11. Eguchi T, Kuwahara T, Sakurai M, et al. LRRK2 and its substrate Rab GTPases are sequentially targeted onto stressed lysosomes and maintain their homeostasis. Proc Natl Acad Sci U S A. 2018;115(39):E9115-E9124.
12. Purlyte E, Dhekne HS, Sarhan AR, et al. Rab29 activation of the Parkinson’s disease-associated LRRK2 kinase. EMBO J. 2019;38(2). doi:10.15252/embj.2018101237
13. Steger M, Tonelli F, Ito G, et al. Phosphoproteomics reveals that Parkinson’s disease kinase LRRK2 regulates a subset of Rab GTPases. Elife. 2016;5. doi:10.7554/eLife.12813
14. Henderson MX, Sedor S, McGeary I, et al. Glucocerebrosidase Activity Modulates Neuronal Susceptibility to Pathological α-Synuclein Insult. Neuron. 2020;105(5):822-836.e7.
15. Pierce S, Coetzee GA. Parkinson’s disease-associated genetic variation is linked to quantitative expression of inflammatory genes. PLoS One. 2017;12(4):e0175882.
16. Caggiu E, Arru G, Hosseini S, et al. Inflammation, Infectious Triggers, and Parkinson’s Disease. Front Neurol. 2019;10:122.
17. Chang D, Nalls MA, Hallgrímsdóttir IB, et al. A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat Genet. 2017;49(10):1511-1516.
18. Karch CM, Goate AM. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry. 2015;77(1):43-51.
19. Lambert JC, Ibrahim-Verbaas CA, Harold D, et al. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. 2013;45(12):1452-1458.
20. Jonsson T, Stefansson H, Steinberg S, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med. 2013;368(2):107-116.
21. Keren-Shaul H, Spinrad A, Weiner A, et al. A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease. Cell. 2017;169(7):1276-1290.e17.
22. Krasemann S, Madore C, Cialic R, et al. The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases. Immunity. 2017;47(3):566-581.e9.
23. Katsouri L, Lim YM, Blondrath K, et al. PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model. Proc Natl Acad Sci U S A. 2016;113(43):12292-12297.
24. Ramesh N, Pandey UB. Autophagy Dysregulation in ALS: When Protein Aggregates Get Out of Hand. Front Mol Neurosci. 2017;10:263.
25. Renton AE, Chiò A, Traynor BJ. State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci. 2014;17(1):17-23.
26. Turner MR, Cagnin A, Turkheimer FE, et al. Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: an [11C](R)-PK11195 positron emission tomography study. Neurobiol Dis. 2004;15(3):601-609.
27. Henkel JS, Engelhardt JI, Siklós L, et al. Presence of dendritic cells, MCP-1, and activated microglia/macrophages in amyotrophic lateral sclerosis spinal cord tissue. Ann Neurol. 2004;55(2):221-235.
28. Lall D, Baloh RH. Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia. J Clin Invest. 2017;127(9):3250-3258.
29. Vissers MFJM, Heuberger JAAC, Groeneveld GJ. Targeting for Success: Demonstrating Proof-of-Concept with Mechanistic Early Phase Clinical Pharmacology Studies for Disease-Modification in Neurodegenerative Disorders. Int J Mol Sci. 2021;22(4). doi:10.3390/ijms22041615
30. Beach TG. A Review of Biomarkers for Neurodegenerative Disease: Will They Swing Us Across the Valley? Neurol Ther. 2017;6(Suppl 1):5-13.
31. Cohen AF, Burggraaf J, van Gerven JMA, Moerland M, Groeneveld GJ. The use of biomarkers in human pharmacology (Phase I) studies. Annu Rev Pharmacol Toxicol. 2015;55:55-74.
32. Tardiff DF, Lucas M, Wrona I, et al. Non-clinical Pharmacology of YTX-7739: a Clinical Stage Stearoyl-CoA Desaturase Inhibitor Being Developed for Parkinson’s Disease. Mol Neurobiol. 2022;59(4):2171-2189.
33. Nuber S, Chung CY, Tardiff DF, et al. A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity. Neurotherapeutics. Published online April 20, 2022. doi:10.1007/s13311-022-01199-7
34. den Heijer JM, Kruithof AC, van Amerongen G, et al. A randomized single and multiple ascending dose study in healthy volunteers of LTI-291, a centrally penetrant glucocerebrosidase activator. Br J Clin Pharmacol. 2021;87(9):3561-3573.
35. Jennings D, Huntwork-Rodriguez S, Henry AG, et al. Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson’s disease. Sci Transl Med. 2022;14(648):eabj2658.
36. Monnet E, Lapeyre G, van Poelgeest E, et al. Evidence of NI-0101 pharmacological activity, an anti-TLR4 antibody, in a randomized phase I dose escalation study in healthy volunteers receiving LPS. Clin Pharmacol Ther. 2017;101(2):200-208.
37. Grievink HW, Jirka SMG, Woutman TD, et al. Antimicrobial Peptide Omiganan Enhances Interferon Responses to Endosomal Toll-Like Receptor Ligands in Human Peripheral Blood Mononuclear Cells. Clin Transl Sci. 2020;13(5):891-895.
38. Vissers MFJM, Heuberger JAAC, Groeneveld GJ, et al. Safety, pharmacokinetics and target engagement of novel RIPK1 inhibitor SAR443060 (DNL747) for neurodegenerative disorders: Randomized, placebo-controlled, double-blind phase I/Ib studies in healthy subjects and patients. Clin Transl Sci. Published online June 1, 2022. doi:10.1111/cts.13317
39. Cai X, Xu Y, Cheung AK, et al. PIKfyve, a class III PI kinase, is the target of the small molecular IL-12/IL-23 inhibitor apilimod and a player in Toll-like receptor signaling. Chem Biol. 2013;20(7):912-921.
40. Khasawneh AH, Garling RJ, Harris CA. Cerebrospinal fluid circulation: What do we know and how do we know it? Brain Circ. 2018;4(1):14-18.
41. Bulat M, Klarica M. Recent insights into a new hydrodynamics of the cerebrospinal fluid. Brain Res Rev. 2011;65(2):99-112.
42. Johanson C, Johanson N. Merging Transport Data for Choroid Plexus with Blood-Brain Barrier to Model CNS Homeostasis and Disease More Effectively. CNS Neurol Disord Drug Targets. 2016;15(9):1151-1180.
43. Sakka L, Coll G, Chazal J. Anatomy and physiology of cerebrospinal fluid. Eur Ann Otorhinolaryngol Head Neck Dis. 2011;128(6):309-316.
44. Green KN, Crapser JD, Hohsfield LA. To Kill a Microglia: A Case for CSF1R Inhibitors. Trends Immunol. 2020;41(9):771-784.
45. Khalil M, Teunissen CE, Otto M, et al. Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol. 2018;14(10):577-589.
46. Byeon SK, Madugundu AK, Jain AP, et al. Cerebrospinal fluid lipidomics for biomarkers of Alzheimer’s disease. Mol Omics. 2021;17(3):454-463.
47. Bader JM, Geyer PE, Müller JB, et al. Proteome profiling in cerebrospinal fluid reveals novel biomarkers of Alzheimer’s disease. Mol Syst Biol. 2020;16(6):e9356.
48. Sokoloff L. Energetics of functional activation in neural tissues. Neurochem Res. 1999;24(2):321-329.
49. Kleinberger G, Brendel M, Mracsko E, et al. The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism. EMBO J. 2017;36(13):1837-1853.
50. Xiang X, Wind K, Wiedemann T, et al. Microglial activation states drive glucose uptake and FDG-PET alterations in neurodegenerative diseases. Sci Transl Med. 2021;13(615):eabe5640.
51. Budd Haeberlein S, Aisen PS, Barkhof F, et al. Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer’s Disease. J Prev Alzheimers Dis. 2022;9(2):197-210.
52. Mintun MA, Lo AC, Duggan Evans C, et al. Donanemab in Early Alzheimer’s Disease. N Engl J Med. 2021;384(18):1691-1704.
53. Honig LS, Vellas B, Woodward M, et al. Trial of Solanezumab for Mild Dementia Due to Alzheimer’s Disease. N Engl J Med. 2018;378(4):321-330.
54. Smart K, Naganawa M, Baldassarri SR, et al. PET Imaging Estimates of Regional Acetylcholine Concentration Variation in Living Human Brain. Cereb Cortex. 2021;31(6):2787-2798.
55. Kim YJ, Ichise M, Ballinger JR, et al. Combination of dopamine transporter and D2 receptor SPECT in the diagnostic evaluation of PD, MSA, and PSP. Mov Disord. 2002;17(2):303-312.
56. Hadoux X, Hui F, Lim JKH, et al. Non-invasive in vivo hyperspectral imaging of the retina for potential biomarker use in Alzheimer’s disease. Nat Commun. 2019;10(1):4227.
57. Mochel F, N’Guyen TM, Deelchand D, et al. Abnormal response to cortical activation in early stages of Huntington disease. Mov Disord. 2012;27(7):907-910.
58. Adanyeguh IM, Rinaldi D, Henry PG, et al. Triheptanoin improves brain energy metabolism in patients with Huntington disease. Neurology. 2015;84(5):490-495.
59. van Diemen MPJ, Hart EP, Abbruscato A, et al. Safety, pharmacokinetics and pharmacodynamics of SBT-020 in patients with early stage Huntington’s disease, a 2-part study. Br J Clin Pharmacol. 2021;87(5):2290-2302.
60. Bouldin TW, Krigman MR. Differential permeability of cerebral capillary and choroid plexus to lanthanum ion. Brain Res. 1975;99(2):444-448.
61. Ferguson RK, Woodbury DM. Penetration of 14C-inulin and 14C-sucrose into brain, cerebrospinal fluid, and skeletal muscle of developing rats. Exp Brain Res. 1969;7(3):181-194.
62. Pardridge WM. Blood-Brain Barrier and Delivery of Protein and Gene Therapeutics to Brain. Front Aging Neurosci. 2019;11:373.
63. Reiber H. Proteins in cerebrospinal fluid and blood: barriers, CSF flow rate and source-related dynamics. Restor Neurol Neurosci. 2003;21(3-4):79-96.
64. Boado RJ, Zhang Y, Zhang Y, Xia CF, Pardridge WM. Fusion antibody for Alzheimer’s disease with bidirectional transport across the blood-brain barrier and abeta fibril disaggregation. Bioconjug Chem. 2007;18(2):447-455.
65. Pardridge WM. Blood-brain barrier endogenous transporters as therapeutic targets: a new model for small molecule CNS drug discovery. Expert Opin Ther Targets. 2015;19(8):1059-1072.
66. Banks WA. The source of cerebral insulin. Eur J Pharmacol. 2004;490(1-3):5-12.
67. Pardridge WM, Eisenberg J, Yang J. Human blood-brain barrier transferrin receptor. Metabolism. 1987;36(9):892-895.
68. Reinhardt RR, Bondy CA. Insulin-like growth factors cross the blood-brain barrier. Endocrinology. 1994;135(5):1753-1761.
69. Demeule M, Currie JC, Bertrand Y, et al. Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector angiopep-2. J Neurochem. 2008;106(4):1534-1544.
70. Golden PL, Maccagnan TJ, Pardridge WM. Human blood-brain barrier leptin receptor. Binding and endocytosis in isolated human brain microvessels. J Clin Invest. 1997;99(1):14-18.
71. Schlachetzki F, Zhu C, Pardridge WM. Expression of the neonatal Fc receptor (FcRn) at the blood-brain barrier. J Neurochem. 2002;81(1):203-206.
72. Boado RJ, Ka-Wai Hui E, Zhiqiang Lu J, Pardridge WM. Insulin receptor antibody-iduronate 2-sulfatase fusion protein: pharmacokinetics, anti-drug antibody, and safety pharmacology in Rhesus monkeys. Biotechnol Bioeng. 2014;111(11):2317-2325.
73. Sonoda H, Morimoto H, Yoden E, et al. A Blood-Brain-Barrier-Penetrating Anti-human Transferrin Receptor Antibody Fusion Protein for Neuronopathic Mucopolysaccharidosis II. Mol Ther. 2018;26(5):1366-1374.
74. Morimoto H, Kida S, Yoden E, et al. Clearance of heparan sulfate in the brain prevents neurodegeneration and neurocognitive impairment in MPS II mice. Mol Ther. 2021;29(5):1853-1861.
75. Giugliani R, Martins AM, So S, et al. Iduronate-2-sulfatase fused with anti-hTfR antibody, pabinafusp alfa, for MPS-II: A phase 2 trial in Brazil. Mol Ther. 2021;29(7):2378-2386.
76. Okuyama T, Eto Y, Sakai N, et al. A Phase 2/3 Trial of Pabinafusp Alfa, IDS Fused with Anti-Human Transferrin Receptor Antibody, Targeting Neurodegeneration in MPS-II. Mol Ther. 2021;29(2):671-679.
77. Ullman JC, Arguello A, Getz JA, et al. Brain delivery and activity of a lysosomal enzyme using a blood-brain barrier transport vehicle in mice. Sci Transl Med. 2020;12(545). doi:10.1126/scitranslmed.aay1163
78. Arguello A, Mahon CS, Calvert MEK, et al. Molecular architecture determines brain delivery of a transferrin receptor-targeted lysosomal enzyme. J Exp Med. 2022;219(3). doi:10.1084/jem.20211057
79. Zhou X, Smith QR, Liu X. Brain penetrating peptides and peptide-drug conjugates to overcome the blood-brain barrier and target CNS diseases. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2021;13(4):e1695.
80. Kurzrock R, Gabrail N, Chandhasin C, et al. Safety, pharmacokinetics, and activity of GRN1005, a novel conjugate of angiopep-2, a peptide facilitating brain penetration, and paclitaxel, in patients with advanced solid tumors. Mol Cancer Ther. 2012;11(2):308-316.
81. Drappatz J, Brenner A, Wong ET, et al. Phase I study of GRN1005 in recurrent malignant glioma. Clin Cancer Res. 2013;19(6):1567-1576.
82. Kariolis MS, Wells RC, Getz JA, et al. Brain delivery of therapeutic proteins using an Fc fragment blood-brain barrier transport vehicle in mice and monkeys. Sci Transl Med. 2020;12(545). doi:10.1126/scitranslmed.aay1359
83. Yin Y, Wang J, Yang M, et al. Penetration of the blood-brain barrier and the anti-tumour effect of a novel PLGA-lysoGM1/DOX micelle drug delivery system. Nanoscale. 2020;12(5):2946-2960.
84. Burks SR, Kersch CN, Witko JA, et al. Blood-brain barrier opening by intracarotid artery hyperosmolar mannitol induces sterile inflammatory and innate immune responses. Proc Natl Acad Sci U S A. 2021;118(18). doi:10.1073/pnas.2021915118
85. Bartus RT, Elliott PJ, Dean RL, et al. Controlled modulation of BBB permeability using the bradykinin agonist, RMP-7. Exp Neurol. 1996;142(1):14-28.
86. Parrish KE, Sarkaria JN, Elmquist WF. Improving drug delivery to primary and metastatic brain tumors: strategies to overcome the blood-brain barrier. Clin Pharmacol Ther. 2015;97(4):336-346.
87. Niu J, Xie J, Guo K, et al. Efficient treatment of Parkinson’s disease using ultrasonography-guided rhFGF20 proteoliposomes. Drug Deliv. 2018;25(1):1560-1569.
88. Lipsman N, Meng Y, Bethune AJ, et al. Blood-brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. Nat Commun. 2018;9(1):2336.
89. Gasca-Salas C, Fernández-Rodríguez B, Pineda-Pardo JA, et al. Blood-brain barrier opening with focused ultrasound in Parkinson’s disease dementia. Nat Commun. 2021;12(1):779.
90. Salahuddin TS, Johansson BB, Kalimo H, Olsson Y. Structural changes in the rat brain after carotid infusions of hyperosmolar solutions. An electron microscopic study. Acta Neuropathol. 1988;77(1):5-13.
91. Rautio J, Kumpulainen H, Heimbach T, et al. Prodrugs: design and clinical applications. Nat Rev Drug Discov. 2008;7(3):255-270.
92. Bakker C, van der Aart J, Hart EP, et al. Safety, pharmacokinetics, and pharmacodynamics of Gln-1062, a prodrug of galantamine. Alzheimers Dement. 2020;6(1):e12093.
93. Hey JA, Yu JY, Versavel M, et al. Clinical Pharmacokinetics and Safety of ALZ-801, a Novel Prodrug of Tramiprosate in Development for the Treatment of Alzheimer’s Disease. Clin Pharmacokinet. 2018;57(3):315-333.
94. Hartley MD, Shokat MD, DeBell MJ, Banerji T, Kirkemo LL, Scanlan TS. Pharmacological Complementation Remedies an Inborn Error of Lipid Metabolism. Cell Chem Biol. 2020;27(5):551-559.e4.
95. Lang AE, Gill S, Patel NK, et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol. 2006;59(3):459-466.
96. Salvatore MF, Ai Y, Fischer B, et al. Point source concentration of GDNF may explain failure of phase II clinical trial. Exp Neurol. 2006;202(2):497-505.
97. Whone A, Luz M, Boca M, et al. Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson’s disease. Brain. 2019;142(3):512-525.
98. Yadav DB, Maloney JA, Wildsmith KR, et al. Widespread brain distribution and activity following i.c.v. infusion of anti-β-secretase (BACE1) in nonhuman primates. Br J Pharmacol. 2017;174(22):4173-4185.
99. Ziegler RJ, Salegio EA, Dodge JC, et al. Distribution of acid sphingomyelinase in rodent and non-human primate brain after intracerebroventricular infusion. Exp Neurol. 2011;231(2):261-271.
100. Berg SL, Chamberlain MC. Systemic chemotherapy, intrathecal chemotherapy, and symptom management in the treatment of leptomeningeal metastasis. Curr Oncol Rep. 2003;5(1):29-40.
101. Finkel RS, Mercuri E, Darras BT, et al. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017;377(18):1723-1732.
102. Mercuri E, Darras BT, Chiriboga CA, et al. Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. N Engl J Med. 2018;378(7):625-635.
103. Chen Y, Liu L. Modern methods for delivery of drugs across the blood-brain barrier. Adv Drug Deliv Rev. 2012;64(7):640-665.
104. Zhang ET, Inman CB, Weller RO. Interrelationships of the pia mater and the perivascular (Virchow-Robin) spaces in the human cerebrum. J Anat. 1990;170:111-123.
105. Iliff JJ, Wang M, Liao Y, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012;4(147):147ra111.
106. Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14(3):133-150.
107. Sallerin-Caute B, Lazorthes Y, Monsarrat B, Cros J, Bastide R. CSF baclofen levels after intrathecal administration in severe spasticity. Eur J Clin Pharmacol. 1991;40(4):363-365.
108. Shafer SL, Eisenach JC, Hood DD, Tong C. Cerebrospinal fluid pharmacokinetics and pharmacodynamics of intrathecal neostigmine methylsulfate in humans. Anesthesiology. 1998;89(5):1074-1088.
109. Wolf DA, Hesterman JY, Sullivan JM, et al. Dynamic dual-isotope molecular imaging elucidates principles for optimizing intrathecal drug delivery. JCI Insight. 2016;1(2):e85311.
110. Papisov MI, Belov VV, Gannon KS. Physiology of the intrathecal bolus: the leptomeningeal route for macromolecule and particle delivery to CNS. Mol Pharm. 2013;10(5):1522-1532.
111. Verma A, Hesterman JY, Chazen JL, et al. Intrathecal 99mTc-DTPA imaging of molecular passage from lumbar cerebrospinal fluid to brain and periphery in humans. Alzheimers Dement. 2020;12(1):e12030.
112. Khani M, Burla GKR, Sass LR, et al. Human in silico trials for parametric computational fluid dynamics investigation of cerebrospinal fluid drug delivery: impact of injection location, injection protocol, and physiology. Fluids Barriers CNS. 2022;19(1):8.
113. Sullivan JM, Mazur C, Wolf DA, et al. Convective forces increase rostral delivery of intrathecal radiotracers and antisense oligonucleotides in the cynomolgus monkey nervous system. J Transl Med. 2020;18(1):309.