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Borek et al. Rare Dis Orphan Drugs J 2023;2:5 https://dx.doi.org/10.20517/rdodj.2022.20 Page 9 of 14

central regulators of many biological processes that are necessary for tissue homeostasis. This complexity
requires a delicate balance between targeting serine proteases to achieve therapeutic benefits while avoiding
disruption to normal tissue function. It is important to note that broad-spectrum inhibition of serine
proteases can be detrimental, as demonstrated by Aprotinin, the administration of which significantly
increases the risk of end-organ damage and death . For safety reasons, a more refined, targeted approach
[120]
needs to be favored. Elafin (NE and PR3 inhibitor) is currently being investigated in a phase 1 clinical trial
for the treatment of PAH (ClinicalTrials.gov Identifier: NCT03522935). Cathepsin C (CtsC) makes another
interesting target for modulating serine-proteases-mediated tissue damage and inflammation, as it is an
upstream activator of NSPs, tryptase, chymase, and granzymes. Brensocatib, a CtsC inhibitor, has recently
[121]
been confirmed as safe and effective in phase 2 clinical trials involving bronchiectasis patients . Given the
strong implication of neutrophil and MC serine proteases in the development of PAH, targeting CtsC to
reduce proteolytic activity in the tissue - by preventing the conversion of zymogens to active enzymes -
[45]
emerges as a potential therapy to treat PAH. Genetic inactivation of CtsC in humans leads to Papillon-Lefè
vre syndrome (PLS, OMIM: 245000), an autosomal recessive disorder in which NSP activity is minimal or
[122]
absent . Because the clinical consequences of this disorder are mild, small molecule inhibitors targeting
CtsC activity are considered safe and represent an attractive therapeutic strategy to modulate NSP-mediated
tissue damage and inflammation. However, given that neutrophil NSPs and MC serine proteases have a
broad range of targets and affect various aspects of inflammation and tissue damage, inhibiting their activity
could have immunomodulatory and anti-remodeling effects not only in PAH but also in many other
diseases.

DECLARATIONS
Authors’ contributions
Wrote and edited the manuscript: Borek I
Provided a critical review of the manuscript: Kwapiszewska G

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
Both authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Copyright
© The Authors 2023.

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