The Barriers Of

Gene Therapy FOR

Cystic Fibrosis

Spirovant Sciences is a Philadelphia, PA gene therapy company developing treatments and cures for respiratory diseases including cystic fibrosis.


Cystic Fibrosis (CF)

Cystic fibrosis is a life-threatening, autosomal recessive genetic disease with no cure. There are an estimated 82,000 cystic fibrosis patients worldwide. Cystic fibrosis is caused by loss-of-function mutations of the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR), a channel that conducts chloride and bicarbonate ions across epithelial cell membranes. Over 100 mutations in the CFTR gene have been described to be pathogenic. Derangement of CFTR causes accumulation of abnormally thickened mucus, which subsequently results in poor mucociliary transport and bacterial infections. Although the disease affects several organs, it mostly leads to death from respiratory failure.

The standard of care for cystic fibrosis includes therapies that address symptoms of the disease, such as bronchodilators, mucolytics, antibiotics and chest percussion. There are also small molecule correctors of CFTR trafficking or potentiators of impaired ion channel activity for many individuals with CF. However, none of the current treatments prevent continued disease progression and CFTR modulators are not effective for individuals with mutations not indicated for CFTR modulators and individuals with minimal benefit to CFTR modulators. Gene therapy is an attractive curative option for individuals who do not benefit from or have insufficient benefits from CFTR modulators, and ultimately for all individuals with CF independent of their mutations



Spirovant’s proprietary Adeno-Associated Virus (AAV) platform is designed for the introduction of a fully functional copy of the CFTR gene into target cells of the respiratory system to address the underlying cause of CF. It is delivered as an aerosolized therapy and has been optimized to overcome challenges that have previously limited the clinical viability of gene therapy for cystic fibrosis. Access to the AAV platform provides Spirovant with the unique opportunity to design tailored therapies for cystic fibrosis and other respiratory diseases. Our approach is mutation-agnostic for the treatment of CF.



Spirovant has developed innovations that collectively have the potential to overcome challenges that have previously limited the clinical viability of gene therapy for cystic fibrosis. Currently, Spirovant has an aerosolized Adeno-Associated Virus (AAV) gene therapy platform that has been optimized to be highly tropic to human airway epithelia.

AAV Platform

Adeno-Associated Viruses (AAV) are small, replication-defective viruses that infect human cells. AAV can infect dividing and non-dividing cells, do not cause disease and elicit only a very mild immune response, which among other attributes, make them attractive candidates for gene therapy. Transduction of cells with AAV is a multi-step process starting with binding to the cell surface, uptake, intracellular processing and migration into the cell nucleus, where gene transcription takes place. The AAV genome persists in an extrachromosomal state in the nucleus of the host cell. It does not integrate into the cellular genome. Small molecules that inhibit the host cell proteasome activity have been shown to strongly enhance the translocation of the AAV genome from the cytoplasm into the nucleus, resulting in much higher levels of transgene transcription.

Spirovant’s AAV platform consists of a novel AAV capsid, AAV2.5T, that has been selected for its high tropism to the apical side of cultured human airway epithelial cells, a highly optimized transgene payload flanked by novel regulatory elements, which collectively drive high expression of functional CFTR protein and subsequent correction of the CF phenotype in human airway epithelia.



Spirovant’s development programs have created a robust pipeline of drug candidates for the treatment of serious life-threatening lung diseases.

Cystic Fibrosis
SP-101 (AAV-hCFTR∆R)
Therapeutic Approach
Restore CFTR Function
Therapy Method
Inhaled therapy
Single Dose Administration

SP-101 - a novel inhaled AAV gene therapy to treat CF

Previous attempts to treat CF with AAV gene therapies were well tolerated but hampered by poor efficacy. Spirovant’s lead candidate SP-101 is optimized to overcome historical barriers. SP-101 is composed of a novel AAV capsid, AAV2.5T, that has been selected for its high tropism to the apical side of cultured human airway epithelial cells (Excoffon KJ, et al. Proc Natl Acad Sci U S A. 2009;106(10):3865-3870), which is present on the luminal side of the airways targeted by the inhalation route. It further contains a human CFTR minigene (hCFTR∆R) with regulatory elements (Ostedgaard LS, et al. Proc Natl Acad Sci U S A. 2002;99(5):3093-3098 Yan Z, et al. Hum Gene Ther. 2015;26(6):334-346) that efficiently drive hCFTR∆R expression in human airway epithelial cells.

Preclinical data indicate that the co-administration of doxorubicin, a small molecule chemotherapeutic and proteasome inhibitor, is critical for the correction of CF. Doxorubicin has been shown to strongly increase the production of functional CFTR protein by facilitating the translocation of AAV genomes into the cell nucleus (Yan Z, et al. J Virol. 2004;78(6):2863-2874 Zhang LN, et al. Mol Ther. 2004;10(6):990-1002). Inhaled administration of SP-101 and doxorubicin to CF ferrets resulted in efficient pulmonary hCFTR∆R expression, suggesting that accumulated mucus is not an additional barrier to SP-101. In addition, hCFTR∆R expression increased with increasing doses of SP-101 and doxorubicin and was durable (NACFC 2021 poster and presentation). Spirovant is the only company developing inhaled AAV gene therapy in concert with a small molecule transduction augmenter. The US and EMA granted SP-101 orphan drug designation and additionally, the US granted SP-101 rare pediatric disease designation.

Undisclosed (AAV)
Therapeutic Approach
Therapy Method