A rare genetic respiratory disease affecting the tiny structures in the lungs that filter air is the target of promising new gene therapies delivered directly to the lungs via an inhaler. Two women-led companies are at the forefront of developing these novel mRNA drugs to fight primary ciliary dyskinesia (PCD), a potentially debilitating disease that makes patients vulnerable to severe infections and organ damage.
Both ReCode Therapeutics, led by co-founder and CEO Dr. Shehnaaz Suliman, and Translate Bio, founded by Dr. Jeannie T. Lee and recently acquired by pharmaceutical giant Sanofi in 2021, have targeted mRNA-based treatments for PCD in the pipeline. mRNA therapies being developed by these companies and others have the potential to prevent and treat dozens of diseases of the respiratory system.
mRNA-based therapies tend to be faster and more cost-effective to design and test than other approaches. But the RNA’s instability requires creativity to prevent it from degrading before it reaches its target. ReCode and Translate Bio’s investigational therapies use lipid nanoparticles (LNPs) to envelop and stabilize the mRNA as it carries it to a target tissue, the same technology used by mRNA COVID-19 vaccines. This technique enables the safe delivery of mRNA encoding healthy genes straight to the tissues that lack them. Notably, both companies’ potential therapies are administered by inhaler, allowing them to reach the lungs without interacting with other tissues.
Primary Ciliary Dyskinesia (PCD)
In people with PCD, genetic mutations impair the function of cilia, small hair-like structures that move fluid and particles in the body. In the respiratory system, cilia help filter bacteria, viruses, and other dangerous particles out of the lungs and airways. When these cilia don’t function properly, harmful substances can accumulate in the lungs, causing a build-up of mucus, chronic cough, and infections.
There is currently no cure for PCD. Patients are treated for symptoms, with the goal of keeping the airways clear, preventing infections, and slowing disease progression. Even with treatment, people with PCD are prone to frequent and potentially serious lung, sinus, and ear infections.
The rarity of the disease and the difficulty of targetting therapies to the respiratory system have limited research into potential PCD treatments. However, innovative precision gene therapies that can be drugs directly to the lungs may revolutionize how PCD is managed.
ReCode Therapeutics & Translate Bio (Sanofi Subsidiaries)
ReCode Therapeutics and Translate Bio, now a Sanofi subsidiary, are each developing RNA-based therapies for PCD that target DNAI1. The gene is involved in mucociliary clearance, a self-cleaning process in the respiratory system to clear particles from the lung and airways. DNAI1 mutations, which account for up to 10 percent of all PCD cases, reduce cilia’s ability to function properly and perform this viral process to the health of the lungs. These therapies deliver mRNA that encodes functional DNAI1 protein directly to the respiratory tissue to restore mucociliary clearance.
As a pioneer in the mRNA vaccine field, it’s not surprising that Translate Bio has multiple LNP-based mRNA therapies in development. The company’s approach uses proprietary LNPs that release DNAI1 only after entering target cells. In preliminary studies in mice, the drug increased DNAI1 expression in the ciliated bronchial cells when delivered to the lungs by inhalation. Importantly, the drug was able to orient itself specifically in the cilia, an indication of the precision of the drug’s targeting.
What makes ReCode’s novel therapy unique is its first-in-class Selective Organ Targeting (SORT) LNP platform, which was included in Nature’s list of Seven technologies to watch in 2022. SORT LNPs differ from traditional LNPs by the presence of an additional, unique lipid that the body can “sort,” and ensure that only the correct cells are taking up the drug.
A preclinical trial found that the drug induced steady expression of DNAI1 protein in the cilia of cultured human bronchial endothelial cells for up to two weeks after the treatment. Moreover, the inhaled treatment rescued cilia function in a mouse model of PCD. The results are promising for the investigational therapy, which is expected to enter clinical trial later this year. ReCode has had similar success with its inhaled cystic fibrosis therapy, which is also set to begin clinical trials this year. The company has received a $15 million investment from the Cystic Fibrosis Foundation to help support the drug’s development.
Companies with Inhaled LNP-based mRNA Therapies in Pipeline
Other companies are using similar approaches to develop vaccines and treatments for lung and respiratory diseases. Pharmaceutical companies Vertex and SpliSense both have experimental inhaled LNP-based mRNA therapies for cystic fibrosis entering Phase 1 trials this year. German biotech company Ethris raised 26.3 million last year to support its pipeline of inhaled LNP-based mRNA therapies for PCD and other respiratory diseases. Meanwhile, the North Carolina-based start-up Xsome Biotech completed successful preclinical testing of an inhaled mRNA COVID-19 vaccine using LNP technology that specifically targets the lungs. The method is not without its limitations. The structure and physical barriers of the lungs and airways can impede drug delivery. The respiratory system is designed to keep out foreign particles. Ensuring that drugs are not cleared from the airways either by cilia or pulmonary immune cells may prove a challenge in developing these therapies.