Login Register Cart 0
Review Article

Nanoparticle Based Gene Therapy Approach: A Pioneering Rebellion in the Management of Psychiatric Disorders

Author(s): Saleha Rehman, Bushra Nabi, Faheem Hyder Pottoo, Sanjula Baboota and Javed Ali*

Volume 20, Issue 3, 2020

Page: [164 - 173] Pages: 10

DOI: 10.2174/1566523220666200607185903

Price: $65

Abstract

The neuropsychiatric illnesses have been enigmatic, with no effective treatment to date. The complexity and heterogeneity of psychiatric disorders are daunting for the development of novel treatment modalities. The conventional treatment approaches are less effective and are associated with several side effects, thus creating the need for the development of more innovative strategies. Since psychiatric disorders are known to exhibit genetic linkage, gene therapy has created an interest among the researchers worldwide. The delivery of nucleic acids is a complex process requiring the transport of genetic material across various intracellular and extracellular barriers to reach the target cells eliciting the transfection process. Therefore, the identification or development of the delivery system for nucleic acid delivery still remains the challenge. Viral vectors are quite effective but are associated with toxicity and side effects. With the rapid advancement in the field of nanotechnology, nanosized materials were identified to be the perfect candidate for nonviral vectors in gene delivery. The biggest advantage of nanoparticles is that their surface can be engineered in many possible ways to deliver the drugs directly to the target site. Although gene therapy has already been established as an innovative treatment modality for several neurological diseases, its use in psychiatry still warrants more investigations for its translation into clinical use. The present manuscript discusses the prospects of gene therapy in psychiatric disorders, their benefits, and pitfalls. The review embarks upon the importance of nanoparticle-based gene therapy for effective management of psychiatric disorders.

Keywords: Psychiatric disorders, BDNF, CRISPR, RNA, lipid nanoparticles, mesenchymal cells.

« Previous Next »
Graphical Abstract

[1]
Sullivan PF, Geschwind DH. Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders. Cell 2019; 177(1): 162-83.
[http://dx.doi.org/10.1016/j.cell.2019.01.015] [PMID: 30901538]
[2]
Charlson F, van Ommeren M, Flaxman A, Cornett J, Whiteford H, Saxena S. New WHO prevalence estimates of mental disorders in conflict settings: a systematic review and meta-analysis. Lancet 2019; 394(10194): 240-8.
[http://dx.doi.org/10.1016/S0140-6736(19)30934-1] [PMID: 31200992]
[3]
Gelfand Y, Kaplitt MG. Gene therapy for psychiatric disorders World Neurosurg 2013; 80(3-4): S32-e11-8.
[http://dx.doi.org/10.1016/j.wneu.2012.12.028]
[4]
Leinenga G, Langton C, Nisbet R, Götz J. Ultrasound treatment of neurological diseases- current and emerging applications. Nat Rev Neurol 2016; 12(3): 161-74.
[http://dx.doi.org/10.1038/nrneurol.2016.13] [PMID: 26891768]
[5]
de Haan P, Klein HC, ’t Hart BA. Autoimmune aspects of neurodegenerative and psychiatric diseases: a template for innovative therapy. Front Psychiatry 2017; 8: 46.
[http://dx.doi.org/10.3389/fpsyt.2017.00046] [PMID: 28421005]
[6]
Ahmad MA, Pottoo FH, Akbar M. Gene therapy repairs for the epileptic brain: potential for treatment and future directions. Curr Gene Ther 2020; 19(6): 367-75.
[http://dx.doi.org/10.2174/1566523220666200131142423] [PMID: 32003688]
[7]
Lee SH, Ripke S, Neale BM, et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 2013; 45(9): 984-94.
[http://dx.doi.org/10.1038/ng.2711] [PMID: 23933821]
[8]
Ripke S, Wray NR, Lewis CM, et al. A mega-analysis of genome-wide association studies for major depressive disorder. Mol Psychiatry 2013; 18(4): 497-511.
[http://dx.doi.org/10.1038/mp.2012.21] [PMID: 22472876]
[9]
Chen J, Guo Z, Tian H, Chen X. Production and clinical development of nanoparticles for gene delivery. Mol Ther Methods Clin Dev 2016; 3: 16023.
[http://dx.doi.org/10.1038/mtm.2016.23] [PMID: 27088105]
[10]
Zhao H, Ding R, Zhao X, et al. Graphene-based nanomaterials for drug and/or gene delivery, bioimaging, and tissue engineering. Drug Discov Today 2017; 22(9): 1302-17.
[http://dx.doi.org/10.1016/j.drudis.2017.04.002] [PMID: 28869820]
[11]
Choi YS, Lee MY, David AE, et al. Nanoparticles for gene delivery: therapeutic and toxic effects. Mol Cell Toxicol 2014; 10: 1-8.
[http://dx.doi.org/10.1007/s13273-014-0001-3]
[12]
Soleimani M, Zaabi AM, Merheb M, et al. Nanoparticles in gene therapy. Int J Integr Biol 2016; 17(1): 7-16.
[13]
Yin H, Kanasty RL, Eltoukhy AA, Vegas AJ, Dorkin JR, Anderson DG. Non-viral vectors for gene-based therapy. Nat Rev Genet 2014; 15(8): 541-55.
[http://dx.doi.org/10.1038/nrg3763] [PMID: 25022906]
[14]
Spuch C, Saida O, Navarro C. Advances in the treatment of neurodegenerative disorders employing nanoparticles. Recent Pat Drug Deliv Formul 2012; 6(1): 2-18.
[http://dx.doi.org/10.2174/187221112799219125] [PMID: 22272933]
[15]
Williford JM, Wu J, Ren Y, Archang MM, Leong KW, Mao HQ. Recent advances in nanoparticle-mediated siRNA delivery. Annu Rev Biomed Eng 2014; 16: 347-70.
[http://dx.doi.org/10.1146/annurev-bioeng-071813-105119] [PMID: 24905873]
[16]
Wong HL, Wu XY, Bendayan R. Nanotechnological advances for the delivery of CNS therapeutics. Adv Drug Deliv Rev 2012; 64(7): 686-700.
[http://dx.doi.org/10.1016/j.addr.2011.10.007] [PMID: 22100125]
[17]
Gao H. Progress and perspectives on targeting nanoparticles for brain drug delivery. Acta Pharm Sin B 2016; 6(4): 268-86.
[http://dx.doi.org/10.1016/j.apsb.2016.05.013] [PMID: 27471668]
[18]
Karim R, Palazzo C, Evrard B, Piel G. Nanocarriers for the treatment of glioblastoma multiform: Current state-of-the-art. J Control Release 2016; 227: 23-37.
[http://dx.doi.org/10.1016/j.jconrel.2016.02.026] [PMID: 26892752]
[19]
Hassanzadeh P, Atyabi F, Dinarvand R. Application of modelling and nanotechnology-based approaches: The emergence of breakthroughs in theranostics of central nervous system disorders. Life Sci 2017; 182: 93-103.
[http://dx.doi.org/10.1016/j.lfs.2017.06.001] [PMID: 28583367]
[20]
Yan S, Tu Z, Li S, Li XJ. Use of CRISPR/Cas9 to model brain diseases. Prog Neuropsychopharmacol Biol Psychiatry 2018; 81: 488-92.
[http://dx.doi.org/10.1016/j.pnpbp.2017.04.003] [PMID: 28392484]
[21]
Terrillion CE, Francis TC, Puche AC, Lobo MK, Gould TD. Decreased nucleus accumbens expression of psychiatric disorder risk gene cacna1c promotes susceptibility to social stress. Int J Neuropsychopharmacol 2017; 20(5): 428-33.
[http://dx.doi.org/10.1093/ijnp/pyw112] [PMID: 28165117]
[22]
Bewernick BH, Hurlemann R, Matusch A, et al. Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression. Biol Psychiatry 2010; 67(2): 110-6.
[http://dx.doi.org/10.1016/j.biopsych.2009.09.013] [PMID: 19914605]
[23]
Sapolsky RM. Gene therapy for psychiatric disorders. Am J Psychiatry 2003; 160(2): 208-20.
[http://dx.doi.org/10.1176/appi.ajp.160.2.208] [PMID: 12562564]
[24]
Del Pozo-Rodríguez A, Solinís MÁ, Rodríguez-Gascón A. Applications of lipid nanoparticles in gene therapy. Eur J Pharm Biopharm 2016; 109: 184-93.
[http://dx.doi.org/10.1016/j.ejpb.2016.10.016] [PMID: 27789356]
[25]
Dizaj SM, Jafari S, Khosroushahi AY. A sight on the current nanoparticle-based gene delivery vectors. Nanoscale Res Lett 2014; 9(1): 252.
[http://dx.doi.org/10.1186/1556-276X-9-252] [PMID: 24936161]
[26]
Chen W, Deng W, Goldys EM. Light-Triggerable Liposomes for Enhanced Endolysosomal Escape and Gene Silencing in PC12 Cells. Mol Ther Nucleic Acids 2017; 7: 366-77.
[http://dx.doi.org/10.1016/j.omtn.2017.04.015] [PMID: 28624212]
[27]
Ramamoorth M, Narvekar A. Non viral vectors in gene therapy- an overview. J Clin Diagn Res 2015; 9(1): GE01-6.
[http://dx.doi.org/10.7860/JCDR/2015/10443.5394] [PMID: 25738007]
[28]
Choong CJ, Baba K, Mochizuki H. Gene therapy for neurological disorders. Expert Opin Biol Ther 2016; 16(2): 143-59.
[http://dx.doi.org/10.1517/14712598.2016.1114096] [PMID: 26642082]
[29]
Molla MR, Levkin PA. Combinatorial approach to nanoarchitectonics for nonviral delivery of nucleic acids. Adv Mater 2016; 28(6): 1159-75.
[http://dx.doi.org/10.1002/adma.201502888] [PMID: 26608939]
[30]
Arteta YM, Kjellman T, Bartesaghi S, et al. Successful reprogramming of cellular protein production through mRNA delivered by functionalized lipid nanoparticles. Proc Natl Acad Sci USA 2018; 115(15): E3351-60.
[http://dx.doi.org/10.1073/pnas.1720542115] [PMID: 29588418]
[31]
Gwak S-J, Yun Y, Yoon DH, Kim KN, Ha Y. Therapeutic use of 3β-[N-(N′,N′-Dimethylaminoethane) Carbamoyl] cholesterol-modified plga nanospheres as gene delivery vehicles for spinal cord injury. PLoS One 2016; 11(1)e0147389
[http://dx.doi.org/10.1371/journal.pone.0147389] [PMID: 26824765]
[32]
Fernandes AR, Chari DM, Part II, Part II. Functional delivery of a neurotherapeutic gene to neural stem cells using minicircle DNA and nanoparticles: Translational advantages for regenerative neurology. J Control Release 2016; 238: 300-10.
[http://dx.doi.org/10.1016/j.jconrel.2016.06.039] [PMID: 27369863]
[33]
Mastorakos P, Zhang C, Berry S, et al. Highly PEGylated DNA nanoparticles provide uniform and widespread gene transfer in the brain. Adv Healthc Mater 2015; 4(7): 1023-33.
[http://dx.doi.org/10.1002/adhm.201400800] [PMID: 25761435]
[34]
Yurek DM, Hasselrot U, Cass WA, Sesenoglu-Laird O, Padegimas L, Cooper MJ. Age and lesion-induced increases of GDNF transgene expression in brain following intracerebral injections of DNA nanoparticles. Neuroscience 2015; 284: 500-12.
[http://dx.doi.org/10.1016/j.neuroscience.2014.10.026] [PMID: 25453772]
[35]
Rao S, Morales AA, Pearse DD. The comparative utility of viromer red and lipofectamine for transient gene introduction into glial cells. BioMed Res Int 2015; 2015458624
[http://dx.doi.org/10.1155/2015/458624] [PMID: 26539498]
[36]
Li GF, Wang JC, Feng XM, Liu ZD, Jiang CY, Yang JD. Preparation and testing of quaternized chitosan nanoparticles as gene delivery vehicles. Appl Biochem Biotechnol 2015; 175(7): 3244-57.
[http://dx.doi.org/10.1007/s12010-015-1483-8] [PMID: 25686559]
[37]
Guerrero-Cázares H, Tzeng SY, Young NP, Abutaleb AO, Quiñones-Hinojosa A, Green JJ. Biodegradable polymeric nanoparticles show high efficacy and specificity at DNA delivery to human glioblastoma in vitro and in vivo. ACS Nano 2014; 8(5): 5141-53.
[http://dx.doi.org/10.1021/nn501197v] [PMID: 24766032]
[38]
Huang R, Ke W, Liu Y, et al. Gene therapy using lactoferrin-modified nanoparticles in a rotenone-induced chronic Parkinson model. J Neurol Sci 2010; 290(1-2): 123-30.
[http://dx.doi.org/10.1016/j.jns.2009.09.032] [PMID: 19909981]
[39]
Pottoo FH, Sharma S, Javed MN, et al. Lipid-based nanoformulations in the treatment of neurological disorders. Drug Metab Rev 2020; 52(1): 185-204.
[http://dx.doi.org/10.1080/03602532.2020.1726942] [PMID: 32116044]
[40]
Barnabas W. Drug targeting strategies into the brain for treating neurological diseases. J Neurosci Methods 2019; 311: 133-46.
[http://dx.doi.org/10.1016/j.jneumeth.2018.10.015] [PMID: 30336221]
[41]
Bruun J, Larsen TB, Jølck RI, et al. Investigation of enzyme-sensitive lipid nanoparticles for delivery of siRNA to blood-brain barrier and glioma cells. Int J Nanomedicine 2015; 10: 5995-6008.
[PMID: 26451106]
[42]
Negishi Y, Yamane M, Kurihara N, et al. Enhancement of blood-brain barrier permeability and delivery of antisense oligonucleotides or plasmid dna to the brain by the combination of bubble liposomes and high-intensity focused ultrasound. Pharmaceutics 2015; 7(3): 344-62.
[http://dx.doi.org/10.3390/pharmaceutics7030344] [PMID: 26402694]
[43]
Sharma S, Javed MN, Pottoo FH, et al. Bioresponse inspired nanomaterials for targeted drug and gene delivery. Pharm Nanotechnol 2019; 7(3): 220-33.
[http://dx.doi.org/10.2174/2211738507666190429103814] [PMID: 31486751]
[44]
Mishra S, Sharma S, Javed MN, et al. Bioinspired nanocomposites: applications in disease diagnosis and treatment. Pharm Nanotechnol 2019; 7(3): 206-19.
[http://dx.doi.org/10.2174/2211738507666190425121509] [PMID: 31030662]
[45]
Wright C, Turner JA, Calhoun VD, Perrone-Bizzozero N. Potential impact of miR-137 and its targets in Schizophrenia. Front Genet 2013; 4: 58.
[http://dx.doi.org/10.3389/fgene.2013.00058] [PMID: 23637704]
[46]
Pottoo FH. Barkat Harshita, et al. Nanotechnological based miRNA intervention in the therapeutic management of neuroblastoma. Semin Cancer Biol 2019; S1044-579(19): 30224-X..
[47]
Leung AK, Tam YY, Cullis PR. Lipid nanoparticles for short interfering RNA delivery. Adv Genet 2014; 88: 71-110.
[http://dx.doi.org/10.1016/B978-0-12-800148-6.00004-3] [PMID: 25409604]
[48]
Snead NM, Rossi JJ. RNA interference trigger variants: getting the most out of RNA for RNA interference-based therapeutics. Nucleic Acid Ther 2012; 22(3): 139-46.
[http://dx.doi.org/10.1089/nat.2012.0361] [PMID: 22703279]
[49]
Kanasty RL, Whitehead KA, Vegas AJ, Anderson DG. Action and reaction: the biological response to siRNA and its delivery vehicles. Mol Ther 2012; 20(3): 513-24.
[http://dx.doi.org/10.1038/mt.2011.294] [PMID: 22252451]
[50]
Wan C, Allen TM, Cullis PR. Lipid nanoparticle delivery systems for siRNA-based therapeutics. Drug Deliv Transl Res 2014; 4(1): 74-83.
[http://dx.doi.org/10.1007/s13346-013-0161-z] [PMID: 25786618]
[51]
van der Meel R, Fens MH, Vader P, van Solinge WW, Eniola-Adefeso O, Schiffelers RM. Extracellular vesicles as drug delivery systems: lessons from the liposome field. J Control Release 2014; 195: 72-85.
[http://dx.doi.org/10.1016/j.jconrel.2014.07.049] [PMID: 25094032]
[52]
Cardoso AM, Guedes JR, Cardoso AL, et al. Recent trends in nanotechnology toward cns diseases: lipid-based nanoparticles and exosomes for targeted therapeutic delivery. Int Rev Neurobiol 2016; 130: 1-40.
[http://dx.doi.org/10.1016/bs.irn.2016.05.002] [PMID: 27678173]
[53]
Alvarez-Erviti L, Seow Y, Yin H, Betts C, Lakhal S, Wood MJ. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat Biotechnol 2011; 29(4): 341-5.
[http://dx.doi.org/10.1038/nbt.1807] [PMID: 21423189]
[54]
Autry AE, Monteggia LM. Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 2012; 64(2): 238-58.
[http://dx.doi.org/10.1124/pr.111.005108] [PMID: 22407616]
[55]
Pottoo FH, Tabassum N, Javed MN, et al. Raloxifene potentiates the effect of fluoxetine against maximal electroshock induced seizures in mice. Eur J Pharm Sci 2020; 146105261
[http://dx.doi.org/10.1016/j.ejps.2020.105261] [PMID: 32061655]
[56]
Pottoo FH, Javed MN, Barkat MA, et al. Estrogen and Serotonin: complexity of interactions and implications for epileptic seizures and epileptogenesis. Curr Neuropharmacol 2019; 17(3): 214-31.
[http://dx.doi.org/10.2174/1570159X16666180628164432] [PMID: 29956631]
[57]
Angelova A, Angelov B, Drechsler M, Lesieur S. Neurotrophin delivery using nanotechnology. Drug Discov Today 2013; 18(23-24): 1263-71.
[http://dx.doi.org/10.1016/j.drudis.2013.07.010] [PMID: 23891881]
[58]
Tejeda GS, Díaz-Guerra M. Integral characterization of defective bdnf/trkb signalling in neurological and psychiatric disorders leads the way to new therapies. Int J Mol Sci 2017; 18(2): 268.
[http://dx.doi.org/10.3390/ijms18020268] [PMID: 28134845]
[59]
Géral C, Angelova A, Lesieur S. From molecular to nanotechnology strategies for delivery of neurotrophins: emphasis on brain-derived neurotrophic factor (BDNF). Pharmaceutics 2013; 5(1): 127-67.
[http://dx.doi.org/10.3390/pharmaceutics5010127] [PMID: 24300402]
[60]
Park HY, Kim JH, Sun Kim H, Park CK. Stem cell-based delivery of brain-derived neurotrophic factor gene in the rat retina. Brain Res 2012; 1469: 10-23.
[http://dx.doi.org/10.1016/j.brainres.2012.06.006] [PMID: 22750585]
[61]
Nagahara AH, Merrill DA, Coppola G, et al. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat Med 2009; 15(3): 331-7.
[http://dx.doi.org/10.1038/nm.1912] [PMID: 19198615]
[62]
Obata Y, Ciofani G, Raffa V, et al. Evaluation of cationic liposomes composed of an amino acid-based lipid for neuronal transfection. Nanomedicine (Lond) 2010; 6(1): 70-7.
[http://dx.doi.org/10.1016/j.nano.2009.04.005] [PMID: 19447207]
[63]
Boado RJ, Pardridge WM. The Trojan horse liposome technology for nonviral gene transfer across the blood–brain barrier. J Drug Deliv 2011; 2011296151
[http://dx.doi.org/10.1155/2011/296151] [PMID: 22175028]
[64]
Yurek DM, Flectcher AM, Kowalczyk TH, Padegimas L, Cooper MJ. Compacted DNA nanoparticle gene transfer of GDNF to the rat striatum enhances the survival of grafted fetal dopamine neurons. Cell Transplant 2009; 18(10): 1183-96.
[http://dx.doi.org/10.3727/096368909X12483162196881] [PMID: 19650971]
[65]
Aleynik A, Gernavage KM, Mourad YSh, et al. Stem cell delivery of therapies for brain disorders. Clin Transl Med 2014; 3: 24.
[http://dx.doi.org/10.1186/2001-1326-3-24] [PMID: 25097727]
[66]
Colpo GD, Ascoli BM, Wollenhaupt-Aguiar B, et al. Mesenchymal stem cells for the treatment of neurodegenerative and psychiatric disorders. An Acad Bras Cienc 2015; 87(2): 1435-49.
[http://dx.doi.org/10.1590/0001-3765201520140619] [PMID: 26247151]
[67]
Shwartz A, Betzer O, Kronfeld N, et al. Therapeutic effect of astroglia-like mesenchymal stem cells expressing glutamate transporter in a genetic rat model of depression. Theranostics 2017; 7(10): 2690-703.
[http://dx.doi.org/10.7150/thno.18914] [PMID: 28819456]
[68]
Coquery N, Blesch A, Stroh A, et al. Intrahippocampal transplantation of mesenchymal stromal cells promotes neuroplasticity. Cytotherapy 2012; 14(9): 1041-53.
[http://dx.doi.org/10.3109/14653249.2012.694418] [PMID: 22762522]
[69]
Li L, Hu S, Chen X. Non-viral delivery systems for CRISPR/Cas9-based genome editing: Challenges and opportunities. Biomaterials 2018; 171: 207-18.
[http://dx.doi.org/10.1016/j.biomaterials.2018.04.031] [PMID: 29704747]
[70]
Hsu PD, Lander ES, Zhang F. Development and applications of CRISPR-Cas9 for genome engineering. Cell 2014; 157(6): 1262-78.
[http://dx.doi.org/10.1016/j.cell.2014.05.010] [PMID: 24906146]
[71]
Heidenreich M, Zhang F. Applications of CRISPR-Cas systems in neuroscience. Nat Rev Neurosci 2016; 17(1): 36-44.
[http://dx.doi.org/10.1038/nrn.2015.2] [PMID: 26656253]
[72]
Lee B, Lee K, Panda S, et al. Nanoparticle delivery of CRISPR into the brain rescues a mouse model of fragile X syndrome from exaggerated repetitive behaviours. Nat Biomed Eng 2018; 2(7): 497-507.
[http://dx.doi.org/10.1038/s41551-018-0252-8] [PMID: 30948824]
[73]
Bondì ML, Craparo EF. Solid lipid nanoparticles for applications in gene therapy: a review of the state of the art. Expert Opin Drug Deliv 2010; 7(1): 7-18.
[http://dx.doi.org/10.1517/17425240903362410] [PMID: 20017658]
[74]
Belting M, Sandgren S, Wittrup A. Nuclear delivery of macromolecules: barriers and carriers. Adv Drug Deliv Rev 2005; 57(4): 505-27.
[http://dx.doi.org/10.1016/j.addr.2004.10.004] [PMID: 15722161]
[75]
Montana G, Bondì ML, Carrotta R, et al. Employment of cationic solid-lipid nanoparticles as RNA carriers. Bioconjug Chem 2007; 18(2): 302-8.
[http://dx.doi.org/10.1021/bc0601166] [PMID: 17253655]
[76]
Zhao Y, Huang L. Lipid nanoparticles for gene delivery. Adv Genet 2014; 88: 13-36.
[http://dx.doi.org/10.1016/B978-0-12-800148-6.00002-X] [PMID: 25409602]
[77]
Kumar B, Pandey M, Pottoo FH, Fayaz F, Sharma A, Sahoo PK. Liposomes: Novel Drug Delivery Approach for Targeting Parkinson’s Disease. Curr Pharm Des 2020. Epub a head of print..
[http://dx.doi.org/10.2174/1381612826666200128145124] [PMID: 32003666]
[78]
He X, Yang L, Wang M, et al. Targeting the endocannabinoid/CB1 receptor system for treating major depression through antidepressant activities of curcumin and dexanabinol-loaded solid lipid nanoparticles. Cell Physiol Biochem 2017; 42(6): 2281-94.
[http://dx.doi.org/10.1159/000480001] [PMID: 28848078]
[79]
Huang L, Liu Y. In vivo delivery of RNAi with lipid-based nanoparticles. Annu Rev Biomed Eng 2011; 13: 507-30.
[http://dx.doi.org/10.1146/annurev-bioeng-071910-124709] [PMID: 21639780]

Rights & Permissions Print Cite
Article Metrics
36
1
World Hemophilia Day
© 2024 Bentham Science Publishers | Privacy Policy