Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5642_Библиотеки_им_академика_М_И_Перельмана
.pdf
40.
Yapa SWS, Li J, Porter CJ, Nation RL, Patel K, Mcintosh MP. Population pharmacokinetics
of colistin methanesulfonate in rats: achieving sustained lung concentrations of colistin
for targeting respiratory infections. Antimicrob Agents Chemother. 2013;57:5087–95.
https:// doi. org/ 10. 1128/ AAC. 01127-13.
[Crossref][PubMed]
41.
Marchand S, Bouchene S, De Monte M, Guilleminault L, Montharu J, Cabrera M, et al.
Pharmacokinetics of Colistin Methansulphonate (CMS) and Colistin after CMS
Nebulisation in Baboon Monkeys. Pharm Res. 2015;32:3403–14. https:// doi. org/ 10.
1007/ s11095-015-1716-0.
[Crossref][PubMed]
42.
Landersdorfer CB, Nguyen TH, Lieu LT, Nguyen G, Bischof RJ, Meeusen EN, et al.
Substantial targeting advantage achieved by pulmonary administration of colistin
methanesulfonate in a large-animal model. Antimicrob Agents Chemother.
2017;61:e01934–16. https:// doi. org/ 10. 1128/ AAC. 01934-16.
[Crossref][PubMed]
43.
Lu Q, Girardi C, Zhang M, Bouhemad B, Louchahi K, Petitjean O, et al. Nebulized and
intravenous colistin in experimental pneumonia caused by Pseudomonas aeruginosa.
Intensive Care Med. 2010;36:1147–55. https:// doi. org/ 10. 1007/ s00134-010-1879-4.
[Crossref][PubMed]
44.
Marchand S, Gobin P, Brillault J, Baptista S, Adier C, Olivier JC, et al. Aerosol therapy with
colistin methanesulfonate: a biopharmaceutical issue illustrated in rats. Antimicrob
Agents Chemother. 2010;54:3702–7. https:// doi. org/ 10. 1128/ AAC. 00411-10.
[Crossref][PubMed][PubMedCentral]
45.
Lin YW, Zhou QT, Cheah SE, Zhao J, Chen K, Wang J, et al.
Pharmacokinetics/pharmacodynamics of pulmonary delivery of Colistin against
Pseudomonas aeruginosa in a mouse lung infection model. Antimicrob Agents
Chemother. 2017a;61:e02025–16. https:// doi. org/ 10. 1128/ AAC. 02025-16.
[Crossref][PubMed][PubMedCentral]
46.
Tewes F, Brillault J, Gregoire N, Olivier JC, Lamarche I, Adier C, et al. Comparison between
colistin sulfate dry powder and solution for pulmonary delivery. Pharmaceutics.
2020;12:557. https:// doi. org/ 10. 3390/ pharmaceutics120 60557.
[Crossref][PubMed][PubMedCentral]
47.
Lin YW, Zhou QT, Hu Y, Onufrak NJ, Sun S, Wang J, et al. Pulmonary pharmacokinetics of
Colistin following Administration of dry Powder Aerosols in rats. Antimicrob Agents
Chemother. 2017b;61:e00973–17. https:// doi. org/ 10. 1128/ AAC. 00973-17.
[Crossref][PubMed][PubMedCentral]
48.
Park CW, Li X, Vogt FG, Hayes D Jr, Zwischenberger JB, Park ES, et al. Advanced spray-
dried design, physicochemical characterization, and aerosol dispersion performance of
vancomycin and clarithromycin multifunctional controlled release particles for targeted
https://t.me/medicina_free
respiratory delivery as dry powder inhalation aerosols. Int J Pharm. 2013;455:374–92.
https:// doi. org/ 10. 1016/ j. ijpharm. 2013. 06. 047.
[Crossref][PubMed]
49.
Waterer G, Lord J, Hofmann T, Jouhikainen T. Phase I, dose-escalating study of the safety
and pharmacokinetics of inhaled dry-powder vancomycin (AeroVanc) in volunteers and
patients with cystic ibrosis: a new approach to therapy for methicillin-resistant
Staphylococcus aureus. Antimicrob Agents Chemother. 2020;64:e01776–19. https:// doi.
org/ 10. 1128/ AAC. 01776-19.
[Crossref][PubMed][PubMedCentral]
50.
Hayes D Jr, Murphy BS, Mullett TW, Feola DJ. Aerosolized vancomycin for the treatment
of MRSA after lung transplantation. Respirology. 2010;15:184–6. https:// doi. org/ 10.
1111/ j. 1440-1843. 2009. 01647. x.
[Crossref][PubMed]
51.
Dezube R, Jennings MT, Rykiel M, Diener-West M, Boyle MP, Chmiel JF, et al. Eradication
of persistent methicillin-resistant Staphylococcus aureus infection in cystic ibrosis. J
Cyst Fibros. 2019;18:357–63. https:// doi. org/ 10. 1016/ j. jcf. 2018. 07. 005.
[Crossref][PubMed]
52.
Dose Escalation Study of ALX-009 in Healthy Men and Cystic Fibrosis (CF) and Non-CF
Bronchiectasis Patients. https:// ClinicalTrials. gov/ show/ NCT02598999 (2022).
Accessed 28 Feb 2023.
53.
Tunney MM, Payne JE, Mcgrath SJ, Einarsson GG, Ingram RJ, Gilpin DF, et al. Activity of
hypothiocyanite and lactoferrin (ALX-009) against respiratory cystic ibrosis pathogens
in sputum. J Antimicrob Chemother. 2018;73:3391–7. https:// doi. org/ 10. 1093/ jac/
dky357.
[Crossref][PubMed]
54.
Cutone A, Lepanto MS, Rosa L, Scotti MJ, Rossi A, Ranucci S, et al. Aerosolized bovine
Lactoferrin counteracts infection, inlammation and iron dysbalance in a cystic ibrosis
mouse model of pseudomonas aeruginosa chronic lung infection. Int J Mol Sci.
2019;20:2128. https:// doi. org/ 10. 3390/ ijms20092128.
[Crossref][PubMed][PubMedCentral]
55.
Hazlett HF, Hampton TH, Aridgides DS, Armstrong DA, Dessaint JA, Mellinger DL, et al.
Altered iron metabolism in cystic ibrosis macrophages: the impact of CFTR modulators
and implications for Pseudomonas aeruginosa survival. Sci Rep. 2020;10:10935. https://
doi. org/ 10. 1038/ s41598-020-67729-5.
[Crossref][PubMed][PubMedCentral]
56.
Di YP, Lin Q, Chen C, Montelaro RC, Doi Y, Deslouches B. Enhanced therapeutic index of an
antimicrobial peptide in mice by increasing safety and activity against multidrug-
resistant bacteria. Sci Adv. 2020;6:eaay6817. https:// doi. org/ 10. 1126/ sciadv. aay6817.
[Crossref][PubMed][PubMedCentral]
https://t.me/medicina_free
57.
Bracci L, Falciani C, Lelli B, Lozzi L, Runci Y, Pini A, et al. Synthetic peptides in the form of
dendrimers become resistant to protease activity. J Biol Chem. 2003;278:46590–5.
https:// doi. org/ 10. 1074/ jbc. M308615200.
[Crossref][PubMed]
58.
Quercini L, Brunetti J, Riolo G, Bindi S, Scali S, Lampronti I, et al. An antimicrobial
molecule mitigates signs of sepsis in vivo and eradicates infections from lung tissue.
FASEB J. 2020;34:192–207. https:// doi. org/ 10. 1096/ j. 201901896RR.
[Crossref][PubMed]
59.
Pini A, Falciani C, Mantengoli E, Bindi S, Brunetti J, Iozzi S, et al. A novel tetrabranched
antimicrobial peptide that neutralizes bacterial lipopolysaccharide and prevents septic
shock in vivo. FASEB J. 2010;24:1015–22. https:// doi. org/ 10. 1096/ j. 09-145474.
[Crossref][PubMed]
60.
Falciani C, Lozzi L, Pini A, Corti F, Fabbrini M, Bernini A, et al. Molecular basis of
branched peptides resistance to enzyme proteolysis. Chem Biol Drug Des. 2007;69:216–
21. https:// doi. org/ 10. 1111/ j. 1747-0285. 2007. 00487. x.
[Crossref][PubMed]
61.
Sommer P, Fluxa VS, Darbre T, Reymond JL. Proteolysis of peptide dendrimers.
Chembiochem. 2009;10:1527–36. https:// doi. org/ 10. 1002/ cbic. 200900060.
[Crossref][PubMed]
62.
Forde E, Schutte A, Reeves E, Greene C, Humphreys H, Mall M, et al. Differential in vitro
and in vivo toxicities of antimicrobial peptide prodrugs for potential use in cystic
ibrosis. Antimicrob Agents Chemother. 2016;60:2813–21. https:// doi. org/ 10. 1128/ AAC.
00157-16.
[Crossref][PubMed][PubMedCentral]
63.
Forde E, Kelly G, Sweeney L, Fitzgerald-Hughes D, Macloughlin R, Devocelle M. Vibrating
mesh nebulisation of pro-antimicrobial peptides for use in cystic ibrosis. Pharmaceutics.
2019;11:239. https:// doi. org/ 10. 3390/ pharmaceutics110 50239.
[Crossref][PubMed][PubMedCentral]
64.
Forde E, Humphreys H, Greene CM, Fitzgerald-Hughes D, Devocelle M. Potential of host
defense peptide prodrugs as neutrophil elastase-dependent anti-infective agents for
cystic ibrosis. Antimicrob Agents Chemother. 2014;58:978–85. https:// doi. org/ 10. 1128/
AAC. 01167-13.
[Crossref][PubMed][PubMedCentral]
65.
Walton WG, Ahmad S, Little MS, Kim CS, Tyrrell J, Lin Q, et al. Structural features
essential to the antimicrobial functions of human SPLUNC1. Biochemistry.
2016;55:2979–91. https:// doi. org/ 10. 1021/ acs. biochem. 6b00271.
[Crossref][PubMed]
https://t.me/medicina_free
66.
Jiang S, Deslouches B, Chen C, Di ME, Di YP. Antibacterial properties and eficacy of a
novel SPLUNC1-derived antimicrobial peptide, alpha4-short, in a murine model of
respiratory infection. MBio. 2019;10:e00226–19. https:// doi. org/ 10. 1128/ mBio. 00226-
19.
[Crossref][PubMed][PubMedCentral]
67.
Hartl D, Tirouvanziam R, Laval J, Greene CM, Habiel D, Sharma L, et al. Innate immunity
of the lung: from basic mechanisms to translational medicine. J Innate Immun.
2018;10:487–501. https:// doi. org/ 10. 1159/ 000487057.
[Crossref][PubMed][PubMedCentral]
68.
Nijnik A, Madera L, Ma S, Waldbrook M, Elliott MR, Easton DM, et al. Synthetic cationic
peptide IDR-1002 provides protection against bacterial infections through chemokine
induction and enhanced leukocyte recruitment. J Immunol. 2010;184:2539–50. https://
doi. org/ 10. 4049/ jimmunol. 0901813.
[Crossref][PubMed]
69.
Rivas-Santiago B, Castaneda-Delgado JE, Rivas Santiago CE, Waldbrook M, Gonzalez-
Curiel I, Leon-Contreras JC, et al. Ability of innate defence regulator peptides IDR-1002,
IDR-HH2 and IDR-1018 to protect against Mycobacterium tuberculosis infections in
animal models. PLoS One. 2013;8:e59119. https:// doi. org/ 10. 1371/ journal. pone. 0059119.
[Crossref][PubMed][PubMedCentral]
70.
Singh M, Madan T, Waters P, Sonar S, Singh SK, Kamran MF, et al. Therapeutic effects of
recombinant forms of full-length and truncated human surfactant protein D in a murine
model of invasive pulmonary aspergillosis. Mol Immunol. 2009;46:2363–9. https:// doi.
org/ 10. 1016/ j. molimm. 2009. 03. 019.
[Crossref][PubMed]
71.
Moreau-Marquis S, Coutermarsh B, Stanton BA. Combination of hypothiocyanite and
lactoferrin (ALX-109) enhances the ability of tobramycin and aztreonam to eliminate
Pseudomonas aeruginosa bioilms growing on cystic ibrosis airway epithelial cells. J
Antimicrob Chemother. 2015;70:160–6. https:// doi. org/ 10. 1093/ jac/ dku357.
[Crossref][PubMed]
72.
Marshall LJ, Oguejiofor W, Price R, Shur J. Investigation of the enhanced antimicrobial
activity of combination dry powder inhaler formulations of lactoferrin. Int J Pharm.
2016;514:399–406. https:// doi. org/ 10. 1016/ j. ijpharm. 2016. 09. 034.
[Crossref][PubMed]
73.
Bhavsar T, Liu M, Liu X, Cantor J. Aerosolized recombinant human lysozyme enhances the
bactericidal effect of tobramycin in a hamster model of Pseudomonas aeruginosa-
induced pneumonia. Exp Lung Res. 2011;37:536–41. https:// doi. org/ 10. 3109/ 01902148.
2011. 609578.
[Crossref][PubMed]
https://t.me/medicina_free
74.
Gupta PV, Nirwane AM, Nagarsenker MS. Inhalable levoloxacin liposomes complemented
with lysozyme for treatment of pulmonary infection in rats: effective antimicrobial and
Antibioilm strategy. AAPS PharmSciTech. 2018;19:1454–67. https:// doi. org/ 10. 1208/
s12249-017-0945-4.
[Crossref][PubMed]
75.
Matarazzo L, Casilag F, Porte R, Wallet F, Cayet D, Faveeuw C, et al. Therapeutic synergy
between antibiotics and pulmonary toll-like receptor 5 stimulation in antibiotic-
sensitive or -resistant pneumonia. Front Immunol. 2019;10:723. https:// doi. org/ 10.
3389/ immu. 2019. 00723.
[Crossref][PubMed][PubMedCentral]
76.
Qi A, Friend JR, Yeo LY, Morton DA, Mcintosh MP, Spiccia L. Miniature inhalation therapy
platform using surface acoustic wave microluidic atomization. Lab Chip. 2009;9:2184–
93. https:// doi. org/ 10. 1039/ b903575c.
[Crossref][PubMed]
77.
Wang Y, Rezk AR, Khara JS, Yeo LY, Ee PL. Stability and eficacy of synthetic cationic
antimicrobial peptides nebulized using high frequency acoustic waves. Biomicroluidics.
2016b;10:034115. https:// doi. org/ 10. 1063/ 1. 4953548.
[Crossref][PubMed][PubMedCentral]
78.
Yu S, Wang S, Zou P, Chai G, Lin YW, Velkov T, et al. Inhalable liposomal powder
formulations for co-delivery of synergistic ciproloxacin and colistin against multi-drug
resistant gram-negative lung infections. Int J Pharm. 2020;575:118915. https:// doi. org/
10. 1016/ j. ijpharm. 2019. 118915.
[Crossref][PubMed]
79.
Brunaugh AD, Wu T, Kanapuram SR, Smyth HDC. Effect of particle formation process on
characteristics and aerosol performance of Respirable protein powders. Mol Pharm.
2019;16:4165–80. https:// doi. org/ 10. 1021/ acs. molpharmaceut. 9b00496.
[Crossref][PubMed][PubMedCentral]
80.
Ji S, Thulstrup PW, Mu H, Hansen SH, Van De Weert M, Rantanen J, et al. Investigation of
factors affecting the stability of lysozyme spray dried from ethanol-water solutions. Int J
Pharm. 2017;534:263–71. https:// doi. org/ 10. 1016/ j. ijpharm. 2017. 10. 021.
[Crossref][PubMed]
81.
Ferrati S, Wu T, Fuentes O, Brunaugh AD, Kanapuram SR, Smyth HDC. Inluence of
formulation factors on the aerosol performance and stability of lysozyme powders: a
systematic approach. AAPS PharmSciTech. 2018;19:2755–66. https:// doi. org/ 10. 1208/
s12249-018-0980-9.
[Crossref][PubMed]
82.
Graf M, Ziegler CE, Gregoritza M, Goepferich AM. Hydrogel microspheres evading
alveolar macrophages for sustained pulmonary protein delivery. Int J Pharm.
2019;566:652–61. https:// doi. org/ 10. 1016/ j. ijpharm. 2019. 06. 019.
https://t.me/medicina_free
[Crossref][PubMed]
83.
Wallace SJ, Li J, Nation RL, Prankerd RJ, Boyd BJ. Interaction of colistin and colistin
methanesulfonate with liposomes: colloidal aspects and implications for formulation. J
Pharm Sci. 2012;101:3347–59. https:// doi. org/ 10. 1002/ jps. 23203.
[Crossref][PubMed][PubMedCentral]
84.
Falciani C, Zevolini F, Brunetti J, Riolo G, Gracia R, Marradi M, et al. Antimicrobial
peptide-loaded nanoparticles as inhalation therapy for Pseudomonas aeruginosa
infections. Int J Nanomedicine. 2020;15:1117–28. https:// doi. org/ 10. 2147/ IJN. S218966.
[Crossref][PubMed][PubMedCentral]
85.
Nieto-Orellana A, Coghlan D, Rothery M, Falcone FH, Bosquillon C, Childerhouse N, et al.
Dry-powder formulations of non-covalent protein complexes with linear or miktoarm
copolymers for pulmonary delivery. Int J Pharm. 2018;540:78–88. https:// doi. org/ 10.
1016/ j. ijpharm. 2018. 02. 008.
[Crossref][PubMed]
86.
Tenland E, Pochert A, Krishnan N, Umashankar Rao K, Kalsum S, Braun K, et al. Effective
delivery of the anti-mycobacterial peptide NZX in mesoporous silica nanoparticles. PLoS
One. 2019;14:e0212858. https:// doi. org/ 10. 1371/ journal. pone. 0212858.
[Crossref][PubMed][PubMedCentral]
87.
Garcia-Fernandez A, Sancenon F, Martinez-Manez R. Mesoporous silica nanoparticles for
pulmonary drug delivery. Adv Drug Deliv Rev. 2021;177:113953. https:// doi. org/ 10.
1016/ j. addr. 2021. 113953.
[Crossref][PubMed]
https://t.me/medicina_free
(1)
(2)
(3)
(4)
(5)
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
J. Lam, P. C. L. Kwok (eds.), RespiratoryDeliveryofBiologics,NucleicAcids,and
Vaccines, AAPS Introductions in the Pharmaceutical Sciences 8
https://doi.org/10.1007/978-3-031-47567-2_5
PulmonaryDeliveryofNucleicAcids
Gemma Conte
1, 2
, Ivana d’Angelo2, Joschka Mu ller3,
Benjamin Winkeljann
3, 4
, Simone Carneiro3, Olivia M. Merkel
3, 4, 5
and
Francesca Ungaro
1
Department of Pharmacy, University of Napoli Federico II, Naples,
Italy
Di.S.T.A.Bi.F., University of Campania Luigi Vanvitelli, Caserta, Italy
Department of Pharmacy, Pharmaceutical Technology and
Biopharmacy, Ludwig-Maximilians-Universitat Mu nchen, Munich,
Germany
Center for NanoScience (CeNS), Ludwig-Maximilians-Universitat
Mu nchen, Munich, Germany
Institute of Lung Health and Immunity (LHI) and Comprehensive
Pneumology Center (CPC) with the CPC-M bioArchive, Helmholtz
Munich, Member of the German Center for Lung Research (DZL),
Munich, Germany
OliviaM.Merkel
Email:Olivia.merkel@lmu.de
Abstract
Pulmonary diseases affect millions of people worldwide and elicit
symptoms that may evolve into severe conditions. Despite currently
recommended treatments that can successfully control mild to
moderate symptoms, targeted therapy has the potential to improve
serious lung conditions over long time spans. Nucleic acid therapy has
shown remarkable eficacy outcomes against pulmonary diseases
through its mechanism of modulating intracellular gene expression. To
https://t.me/medicina_free
improve the stability of nucleic acid molecules under physiological
conditions and achieve targeted delivery, nucleic acids engineered in
drug-delivery systems and administered by inhalation have been
investigated in recent years. In this chapter, we will review the recent
advances in the inhalation of nucleic acid-based therapies for lung
disorders. The manufacturing of nucleic acid-based nanosystems for
inhalation, as well as their potential to overcome physiological
barriers, will be discussed. Ultimately, we will report on studies on
innovative inhaled formulations that achieved promising results in
animals or in clinical trials and summarize the promising strategies for
pulmonary diseases.
Keywords Inhalation – Nucleic acids – RNA therapeutics – Lung
disorders – Nanoformulation
1 Introd uction
Respiratory diseases are a global burden, with millions of deaths
attributed to pulmonary illnesses and dysfunctions. The constant
progress in the medical ield has oriented attention toward innovative
pharmacological therapies for severe lung diseases. Thus, conventional
therapeutic approaches are currently taking a backseat in favor of
therapeutic nucleic acids (NAs) as viable alternatives for the treatment
of undruggable targets, with the purpose of acting at the intracellular
or even nuclear level.
NAs are biological macromolecules, among which DNA and RNA
separately regulate intracellular gene expression [57]. From a chemical
point of view, NAs are negatively charged macromolecules due to the
presence of a sugar-phosphate backbone composed of single or double
strands characterized by 20 to 1000 bases each. Naked NAs have a halflife of less than an hour in human plasma and are often unable to
penetrate cellular membranes [100]. They suffer nuclease-mediated
degradation as well as inherent chemical instability, which are among
the major bottlenecks in the progress of NA-based pharmaceutical
product development.
Recent studies demonstrate the possibility to chemically-modify
nucleosides to improve metabolic stability, therapeutic outcome, and
https://t.me/medicina_free
reduce immunogenicity [18, 108]. In general, sugar, phosphate-linkage,
and base modiications are commonly used [146]. Sugar-modiied NAs
with a 2′-O-methyl, 2′-O-methoxyethyl, locked nucleic acids (LNA) or
unlocked nucleic acids (UNA) can eficiently decrease immunogenicity
[134], improve speciicity and activity, or reduce site-speciic off-target
effects [19, 50] Phosphate-linkage modiications mainly increase the
stability toward nucleases, resulting in an increased circulation halflife [139]. Base modiication, including the substitution of
pseudouridines, 2-thiouridines, N6-methyladenosines, and 5methylcytidines, results in reduced toxicity and enhanced biological
stability, compared to unmodiied RNA [9, 77].
In parallel to NA chemical modiication, it is paramount to develop
safe and effective delivery systems that are able to carry molecules into
the target cells in an eficient, safe, and reproducible manner. With this
idea in mind, studies investigating local NA delivery for the treatment
of pulmonary diseases have rapidly expanded. The inhalation route
quickly turned into the irst choice to allow direct delivery of NAs to the
target site of action while minimizing systemic exposure. Advanced
delivery strategies based on viral and nonviral vectors are currently
being investigated to improve NAs transport to the target in the lungs
[73, 158]. Although viral vectors have various advantages, their clinical
applicability and approval by regulatory authorities are still hampered
by safety (integration, immunogenicity), manufacturability (consistent
large-scale production), and eficacy concerns [144]. On the other hand,
the rapidly growing sophistication of inhalable nonviral carriers opens
new opportunities aimed at improving NAs’ pulmonary bioavailability
[73].
This chapter will focus on inhaled NA-based therapies for
pulmonary diseases with particular consideration on the hurdles
imposed by the administration route. Moreover, the recent progress in
engineering and producing nucleic acid-based nanoplatforms for
inhalation will be discussed.
2 NucleicAcidTherapeuticsforInha l ation
Since the discovery of NAs, their therapeutic potential in multiple
diseases has been extensively demonstrated. In recent years, NA-based
https://t.me/medicina_free
therapies have become a very attractive therapeutic modality for
various respiratory diseases [98]. Amid them, those having a genetic
origin, such as cystic ibrosis (CF), alpha-1 antitrypsin deiciency
(AATD), and primary ciliary dyskinesia (PCD), may strongly beneit
from inhaled NAs. Nonetheless, NAs, and especially RNA therapeutics,
are also very promising for the treatment of airway inlammation and
hyperresponsiveness and have been suggested for therapy against
chronic obstructive airway disease (COPD) and asthma [153]. These
are also potential ibrotic lung diseases, which represent a large subset
of severe lung diseases with unmet clinical needs, where NA-based
therapies can make the difference, inhibiting pathways that are
otherwise dificult to target [117]. This is the case of idiopathic
pulmonary ibrosis (IPF), an aggressive type of interstitial lung disease
with a very poor prognosis.
NAs of interest for the prevention and treatment of severe lung
diseases can be broadly divided into two functional classes on the
basis of the induced pathway (Fig. 1): (i) gene downregulation (or
protein knockdown) pathway (e.g., antisense oligonucleotides,
microRNA, small interfering RNA); (ii) protein expression pathway
(e.g., messenger RNA). In recent years, the clustered regularly
interspaced short palindromic repeats (CRISPR) and CRISPRassociated protein 9 (Cas9) genome editing system has also emerged
as a versatile tool to achieve gene insertions/deletions, gene
replacements, and single base pair conversions [28].
https://t.me/medicina_free
Соседние файлы в папке Библиотека им академика М.И. Перельмана