BACKGROUND: Ciliopathies are a class of inherited pleiotropic genetic disorders 
in which alterations in cilia assembly, maintenance, and/or function exhibit 
penetrance in the multiple organ systems. Olfactory dysfunction is one such 
clinical manifestation that has been shown in both patients and model organisms. 
Existing therapies for ciliopathies are limited to the treatment or management 
of symptoms. The last decade has seen an increase in potential curative 
therapeutic options including small molecules and biologics. Recent work in 
multiciliated olfactory sensory neurons has demonstrated the capacity of 
targeted gene therapy to restore ciliation in terminally differentiated cells 
and rescue olfactory function. This review will discuss the current 
understanding of the penetrance of ciliopathies in the olfactory system. 
Importantly, it will highlight both pharmacological and biological approaches, 
and their potential therapeutic value in the olfactory system and other ciliated 
tissues.
METHODS: We undertook a structured and comprehensive search of peer-reviewed 
research literature encompassing in vitro, in vivo, model organism, and clinical 
studies. From these publications, we describe the olfactory system, and discuss 
the penetrance of ciliopathies and impact of cilia loss on olfactory function. 
In addition, we outlined the developing therapies for ciliopathies across 
different organ and cell culture systems, and discussed their potential 
therapeutic application to the mammalian olfactory system.
RESULTS: One-hundred sixty-one manuscripts were included in the review, 
centering on the understanding of olfactory penetrance of ciliopathies, and 
discussing the potential therapeutic options for ciliopathies in the context of 
the mammalian olfactory system. Forty-four manuscripts were used to generate a 
table listing the known congenital causes of olfactory dysfunction, with the 
first ten listed are linked to ciliopathies. Twenty-three manuscripts were used 
to outline the potential of small molecules for the olfactory system. Emphasis 
was placed on HDAC6 inhibitors and lithium, both of which were shown to 
stabilize microtubule structures, contributing to ciliogenesis and cilia 
lengthening. Seventy-five manuscripts were used to describe gene therapy and 
gene therapeutic strategies. Included were the implementation of adenoviral, 
adeno-associated virus (AAV), and lentiviral vectors to treat ciliopathies 
across different organ systems and application toward the olfactory system. Thus 
far, adenoviral and AAVmeditated ciliary restoration demonstrated successful 
proof-of-principle preclinical studies. In addition, gene editing, ex vivo gene 
therapy, and transplantation could serve as alternative therapeutic and 
long-term approaches. But for all approaches, additional assessment of vector 
immunogenicity, specificity, and efficacy need further investigation. Currently, 
ciliopathy treatments are limited to symptomatic management with no curative 
options. However, the accessibility and amenability of the olfactory system to 
treatment would facilitate development and advancement of a viable therapy.
CONCLUSION: The findings of this review highlight the contribution of 
ciliopathies to a growing list of congenial olfactory dysfunctions. Promising 
results from other organ systems imply the feasibility of biologics, with 
results from gene therapies proving to be a viable therapeutic option for 
ciliopathies and olfactory dysfunction.