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© 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
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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
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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
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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].
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