Of all the respiratory diseases, one of them – COVID-19 – has been the focus of most of the research and attention over the past two years. While surely justified, this has had the effect of diverting resources away from the study of chronic respiratory diseases that urgently require solutions for clinical unmet needs: chronic obstructive pulmonary disease (COPD), allergic asthma, chronic rhinosinusitis, and cystic fibrosis, among others.
For these chronic respiratory conditions, the lung microbiome is seen as a promising area to explore for the discovery of new therapeutic approaches. Although in healthy individuals the respiratory tract microbiome is relatively sparse (and indeed, the lungs were once thought to be sterile), respiratory pathologies tend to be associated with a greater quantity of microorganisms, including a greater relative abundance of microbial genera such as Haemophilus, Streptococcus, Klebsiella, and Pseudomonas. Researchers are increasingly interested in how specific bacteria may be capable of stimulating both innate and adaptive immune responses via the lungs and other parts of the respiratory tract. So can microbiomes be manipulated with live microbial products to affect the course of chronic respiratory diseases?
Development programs for live biotherapeutic products (LBPs) focused on respiratory health have indeed been moving forward, even while much of the world was focused on COVID-19. These candidates make up a relatively small proportion of LBP development overall, but they represent a promising new approach for those living with chronic respiratory diseases. Several different targets exist for these LBPs: the upper respiratory tract, the lower respiratory tract, and the gastrointestinal tract. Each site has its advantages and challenges as far as LBP development, but all of them appear scientifically justified based on the drug candidate development successes observed to date.
Targeting the Upper Respiratory Tract
The microbes residing in the upper respiratory tract—that is, those in the nose, mouth, and throat—can be sampled in a relatively non-invasive manner for research. From the studies completed so far, it appears the microbiota of the upper respiratory tract may be relevant to acute respiratory pathologies more than chronic ones; however, here is one example of a promising LBP that targets the upper respiratory tract for a chronic condition:
- Researchers at the University of Antwerp in Belgium have discovered and patented a strain of casei that shows antimicrobial activities against various respiratory pathogens, in part due to its excellent adhesion properties to airway, epithelial, and immune cells and barrier enhancing capacity. Administered nasally, it can be a promising treatment for chronic rhinosinusitis and may be licensed to a biotechnology company in the years ahead.
Targeting the Lower Respiratory Tract
The lower respiratory tract (trachea and lungs) has a microbiota that is low density. It appears to originate from microbes in the upper respiratory tract, since there is a constant influx of microbes from the oral cavity, which are then exposed to clearance processes and antimicrobial activity when they reach the lungs.
A major challenge in studying the lower respiratory tract microbiome is the invasiveness of the samples. The ‘gold standard’ samples are long brush or bronchoalveolar lavage samples, collected during bronchoscopy. Sputum samples represent less precise areas but are sometimes taken to represent the lower respiratory tract microbiota. In individuals without pathology, researchers may use minimally invasive throat swabs as a proxy for the lower respiratory tract. Here are some companies aiming to manipulate the lower respiratory tract microbiome for therapeutic effects:
- Pulmobio is a spin-out company from the Centre for Genomic Regulation in Spain, which has a platform that uses genetically engineered lung bacteria to expose antigens or deliver therapeutic agents to the lung in a precise manner. The company has yet to make public its pipeline of candidates, but has disclosed that it is targeting ventilator-associated pneumonia with this technology.
- The US company SciBac is developing LBPs to treat antibiotic resistant disease, with its first two candidates targeting the respiratory tract. Rather than genetically engineering microbes, they use MERGE (Microbial Enhanced Recombinants Generated by Evolution) platform technology to transfer useful genetic traits to beneficial microorganisms. Their candidate SCB-203 is a single strain of modified lactobacillus, inhaled to prevent and treat Pseudomonas aeruginosa infection while reducing the viscosity and volume of mucus in the lungs of those with cystic fibrosis. It works by down-regulating the inflammatory immune response created by the Pseudomonas Another candidate, SCB-211, aims to treat nontuberculous mycobacteria (NTM) lung infection associated with cystic fibrosis and is delivered directly to infected lungs.
- Alveolus Bio is a US-based company working on LBP treatments for COPD and neutrophilic asthma. AB1000 is an LBP candidate for COPD, while AB3000 is for neutrophilic asthma. Both candidates are in preclinical development. The company maintains that inhaled formulations require a lower dose for efficacy, so they use a proprietary resMIT® (Respiratory Microbiota-based Inhaled Therapeutics) Delivery System, in which dry powder particles are delivered by an inhaler to distal lung alveoli.
Targeting the Gut
The ‘gut-lung axis’ is a route of communication between the gastrointestinal tract (gut) and the lungs, and a pathway for microbial signals. The digestive tract and the lungs share a mucosal immune system, which is influenced locally by the microbiota. While the gut-lung axis is a relatively new area of study and many mechanisms are unknown, it appears that bacteria can translocate from the gut to the lung via reflux and micro-aspiration. Moreover, the bloodstream may carry molecules between the lungs and the gut. Here are some examples of companies leveraging the gut-lung axis to treat respiratory-related diseases:
- Siolta, based in the US, is focused on both prevention and treatment of asthma / allergic disease via the gut and immune system. Their ongoing trial on the candidate STMC-103H for prevention of allergic disease in childhood is important because, if successful, it would show the potential for broad modulation of the immune system by a gut-targeted LBP. The company is investigating the same candidate for treating established allergic diseases, including allergic asthma.
- The UK’s 4D pharma has a variety of targets for its LBPs, but one of them is MRx-4DP0004, a single strain gut-targeted therapeutic for partly controlled asthma.
Therapeutics focused on the respiratory microbiome have special challenges – primary among them, the difficulty of obtaining samples and the paucity of microorganisms in the microbiome that is being modulated. But with the above development programs underway, among others, individuals with chronic respiratory diseases may see new solutions before long.