Methods and compositions for treating cystic fibrosis
Inventors
Arnold, Susan • Ballance, David James
Assignees
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Publication Number
US-11052132-B2
Publication Date
2021-07-06
Expiration Date
Abstract
The present disclosure provides a method of treating diseases or disorders associated with CFTR protein dysfunction, including Cystic Fibrosis, by administering stable, long-lasting vasoactive intestinal peptide therapeutic agents. These agents include one or more elastin-like peptides and can be administered at a low-dose.
Core Innovation
The invention relates to treating cystic fibrosis by administering a long-lasting, stable VIP therapeutic formulated with elastin-like peptides (ELPs), including a VIP-ELP fusion protein or a pharmaceutical composition comprising VIP and one or more ELPs. The VIP therapeutics are associated with VPAC1 and VPAC2 biology, and the fusion protein comprises a VPAC2-selective Vasoactive Intestinal Peptide (VIP). The disclosed approach focuses on improving stability and achieving sustained exposure of the VIP therapeutic.
The disclosed compositions use elastin-like peptide structural unit architectures that are based on defined repeat units, including VPGXG repeat architectures, with X selected from Val, Ala, and Gly, and additional ELP repeat and composition options identified as SEQ ID NOs 1–13 and related examples. The stability and sustained release behavior are described through ELP-derived reversible phase-transition matrices, including an inverse phase transition temperature (Tt), supporting long-lasting delivery within the pharmaceutical composition.
The document also describes treatment and performance readouts for cystic fibrosis and CFTR-dysfunction disorders, including sweat chloride, mucus viscosity, fibrosis, and FEV1, together with cellular functional correction measures related to CFTR. Example results described include VIP/VPAC2-associated therapeutics containing specific ELP sequences, including PB1120 (SEQ ID NO:20) and PB1046 (SEQ ID NO:15), that rescue F508del-CFTR function in JME/CF15 cells and correct F508del-CFTR maturation and apical membrane localization. The document further describes enhanced CFTR functional outcomes when co-administered with CFTR modulators such as VX-770 and VX-809.
Claims Coverage
The partial content identifies one independent claim (clm-00001). Its coverage is centered on treating cystic fibrosis using a subcutaneously administered fusion protein that combines a VPAC2-selective VIP with one or more elastin-like peptides (ELPs). The dependent claim set further refines the ELP structure and treatment context, including specific VPGXG architectures and patient and co-therapy limitations.
Subcutaneous VPAC2-selective VIP-ELP fusion protein composition for cystic fibrosis
A method for treating cystic fibrosis comprising subcutaneously administering to a patient in need thereof a pharmaceutical composition comprising a fusion protein comprising a VPAC2-selective Vasoactive Intestinal Peptide (VIP) and one or more elastin-like peptides (ELP).
Within the provided independent claim, the inventive core is subcutaneous administration of a VPAC2-selective VIP fusion protein together with one or more elastin-like peptides for treating cystic fibrosis. The dependent claim refinements in the provided family summary further constrain the ELP repeat architecture and patient genotype (CFTR mutation status and zygosity) and may specify selected co-therapies using named CFTR modulators.
Stated Advantages
Long-lasting, stable VIP therapeutics.
Improved stability through engineered VIP variants.
Sustained-release behavior via ELP-derived reversible phase-transition matrices with an inverse phase transition temperature (Tt).
Rescue of F508del-CFTR function in JME/CF15 cells.
Correction of F508del-CFTR maturation and membrane expression (apical membrane localization).
Enhanced CFTR functional outcomes when co-administered with CFTR modulators such as VX-770 and VX-809.
Documented Applications
Treatment of cystic fibrosis in a patient in need thereof using subcutaneous administration of a VPAC2-selective VIP-ELP fusion protein/pharmaceutical composition.
Treatment of CFTR-dysfunction disorders (described in the partial content as including cystic fibrosis and other CFTR-dysfunction disorders).
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