Leveraging RNA and Delivery Expertise to Treat Pulmonary Diseases

August 18, 2020

By Richard Wooster, Chief Scientific Officer, Translate Bio

While there are many potential applications of our mRNA technology, we have a strong focus on discovering therapeutics for pulmonary diseases, especially given our unique delivery expertise in this area.
We believe that mRNA therapy represents a potential new approach to treating cystic fibrosis (CF), but as we look beyond our encouraging interim results in CF, we also see tremendous potential for mRNA therapeutics to treat multiple other lung diseases.
 With our unique delivery of mRNA therapy through nebulization to the lung, we hope to develop mRNA therapeutics for patients with other pulmonary indications.

 

  • This spotlight delves into how our mRNA and delivery expertise may enable us to treat three other pulmonary diseases: primary ciliary dyskinesia (PCD), pulmonary arterial hypertension (PAH), and idiopathic pulmonary fibrosis (IPF).

  • We aim to address the underlying cause of diseases using our technology to develop novel treatment options to improve the lives of people living with serious, life threatening lung diseases.

Our Next Focus Areas Beyond CF:

Which diseases are we focusing on, and why?

Before discussing how we deliver mRNA for therapeutic purposes, below is a short overview of these additional lung diseases.

Primary ciliary dyskinesia (PCD) is a rare and under-diagnosed genetic condition, related to the abnormal motion of cilia (the tiny hair-like structures that line the respiratory tract). Every day adults breath in about 2,000 gallons of air. The mucus that lines our lungs is one of the earliest lines of defense to the bacteria, dust and other particles that we breath. In healthy lungs the cilia beat in unison, pushing the mucus and trapped material up and out of the lungs. When cilia are absent or beating out of unison, it is a challenge to clear mucous and bacteria from airways. Cilia are complex structures made of multiple proteins. A defect in any one of about 30 genes has been shown to cause PCD, unlike CF which is caused by one defective gene. Five of the genes that cause PCD account for up to half of all patients with this disease. Mutations in the other PCD genes is generally rare. There are approximately 16,000 diagnosed cases of PCD in the United States. With our mRNA platform, we are delivering the mRNA coding for one of the more common defective PCD genes designed to correct the underlying cause of PCD for patients with mutations specifically in this gene.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disorder characterized by thickening, stiffening or scarring – or fibrosis — of tissue within the lungs. There are approximately 83,000 diagnosed cases of IPF in the United States. While there are two approved drugs for the treatment of IPF, these slow the progression of the disease instead of arresting it. With IPF, instead of increasing a desired protein, our approach is focused on delivering a small interfering RNA (siRNA) to the lung to knock down a target protein that has been implicated in IPF. Our intent is to package this into lipid nanoparticles (LNPs) using the same approach as our mRNA therapies.

Pulmonary arterial hypertension (PAH), is a chronic and progressive lung disease, causing arteries in the lungs to become narrow, thick, and stiff — essentially causing high blood pressure in the arteries of the lungs. This makes it difficult for blood to flow through the lungs thereby forcing the heart to work harder. This strain on the heart causes the heart to become enlarged and weak and can lead to heart failure. There are approximately 53,000 diagnosed cases of PAH in the United States. Our intent is to utilize the mRNA platform to produce several protein targets that may potentially slow the progression of the disease.

How We Reach the Lung

This graphic depicts how our mRNA therapy for cystic fibrosis is delivered to a lung cell.

Our goal is to deliver our therapeutic mRNAs directly to the diseased cells in the lung by patients taking our novel medicines via inhalation. mRNA degrades rapidly outside of cells requiring a delivery vehicle that both protects the mRNA as it’s inhaled and successfully transports the mRNA into the lung cells. The vehicle we are using consists of lipids that are formed into lipid nanoparticles (LNPs) that shield and transport the mRNA. We are optimizing our proprietary lipids and LNPs to reach different parts of the lungs, for example towards the top of the lung or deep into the lungs, to deliver to the appropriate lung cells for each disease. The same applies to our siRNA therapies.

By discovering proprietary next-generation delivery technologies, our vision is that an extensive library of novel LNPs will optimize delivery formulations to support lung programs. These LNPs are different from those we use to deliver to other organs such as the liver.

Why Start with Lung Diseases?

The benefits of delivering medicines directly to the lungs, via inhalation, have been studied for more than two hundred years. The first metered-dose inhalers were used in the mid-1950’s; these were widely and successfully used for asthma treatment. This kickstarted a wave of innovation in inhaled therapies through nebulizers that have revolutionized the treatment of lung disease.

Translate Bio continues to innovate; MRT5005 is the first inhaled mRNA therapeutic designed to deliver mRNA coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. For Translate Bio, LNPs play an important role in delivering mRNA to the lung via a handheld nebulizer, but what sets us apart from others is that in doing this, we are hopefully addressing the underlying cause of these lung diseases.

The Future of Inhaled Medicines

Using mRNA therapy, and our MRT platform in particular, to treat lung diseases we believe will be “the future of inhaled medicines,” and one that, we hope, will make all the difference. For the three lung diseases I discussed, and perhaps even more, there is an opportunity to address the underlying cause of the disease, with potential to impact the debilitating effects of the diseases and hopefully help these people live longer lives.