Shaping the future from the small scale: dry powder inhalation of CRISPR-Cas9 lipid nanoparticles for the treatment of lung diseases

ABSTRACT

Introduction

Most lung diseases are serious conditions resulting from genetic and environmental causes associated with high mortality and severe symptoms. Currently, treatments available have a palliative effect and many targets are still considered undruggable. Gene therapy stands as an attractive approach to offering innovative therapeutic solutions. CRISPRCas9 has established a remarkable potential for genome editing with high selectivity to targeted mutations. To ensure high efficacy with minimum systemic exposure, the delivery and administration route are key components that must be investigated.

Areas covered

This review is focused on the delivery of CRISPRCas9 to the lungs, taking advantage of lipid nanoparticles (LNPs), the most clinically advanced nucleic acid carriers. We also aim to highlight the benefits of pulmonary administration as a local delivery route and the use of spray drying to prepare stable nucleic-acid-based dry powder formulations that can overcome multiple lung barriers.

Expert opinion

Exploring the pulmonary administration to deliver CRISPRCas9 loaded in LNPs as a dry powder increases the chances to achieve high efficacy and reduced adverse effects. CRISPRCas9 loaded in LNP-embedded microparticles has not yet been reported in the literature but has the potential to reach and accumulate in target cells in the lung, thus, enhancing overall efficacy and safety.

KEYWORDS:

• Gene therapy
• CRISPR-Cas9
• lipid nanoparticles
• pulmonary administration
• spray drying

Article highlights

• Chronic respiratory diseases are a major concern in public health worldwide; however, treatment options are limited and mostly related to palliative therapy with several adverse effects.

• Pulmonary disorders have an established genetic target. Thus, gene therapy has remarkable potential to address an effective treatment. CRISPR-Cas9 technology enables genome editing by efficiently and selectively correcting mutations through deletions and/or insertion in the DNA.

• CRISPR-Cas9 delivery is crucial to ensure its safe and effective clinical use. Lipid nanoparticles have emerged as promising carriers for efficiently delivering CRISPR-Cas9, in all three forms, to several organs including the lungs.

• The local administration of lipid nanoparticles loading CRISPR-Cas9 enhances therapeutic efficacy and reduces off-target disadvantages. However, to ensure an efficient pulmonary delivery is necessary to overcome the lung biological barriers.

• Spray drying is a powerful technique to produce inhalable sophisticated drug delivery systems with controllable properties. This technique can support the delivery of lipid nanoparticles-CRISPR-Cas9 to the lungs through the airways by ensuring effective, safe, and prolonged gene repair in the targeted tissue.

Declaration of interests

O Merkel is a consultant for PARI Pharma GmbH, AbbVie Deutschland GmbH, AMW GmbH, and an advisory board member for Coriolis Pharma Research GmbH and Carver Biosciences Inc. The other authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was made possible through the generous support of the Alexander von Humboldt Foundation in the form of a Humboldt Postdoctoral Research Fellowship for the author SP Carneiro (2022 – 2024). A Greco thanks the ERASMUS+ mobility scheme project n. 2020-1-IT02-KA103-078342. OM Merkel is funded by ERC-2014-StG – 637830, ERC-2022-POC1-101069308, and the Federal Agency for Disruptive Innovation (BacDefense).