Notes on Engineering Health, December 2020

2020 and Lung Inflammation

2020 has been the year of airway inflammation. Everyone became an immunologist in record time with a specialization in infectious disease and a fellowship in lung damage. Words like cytokine (storms) and R0 have become common lingo in households. The difficulty of understanding and treating airway inflammation, however, was no stranger to the medical community, despite lengthy efforts to better understand targeted therapies to ameliorate its effects. 

The nature and development of airway inflammation in individuals may be driven by numerous factors including pathogenic infections and inhaled particulates. Pathogenic infections are one of the main reasons for acute airway inflammation. The WHO estimates that influenza annually results in between 3 and 5 million cases of severe illness and between 250,000 and 500,000 deaths worldwide. The death toll of the current epidemic is still evolving, but as of publication of this note at least 1.7 million people across the globe have died from COVID-19. Pollution and relatively innocuous inhaled particles such as allergens are also common causes of airway inflammation affecting over 300 million people suffering from asthma globally. 

During any acute airway inflammation attack, an active inflammation response and an appropriately efficient resolution are equally important. Indeed, the inability to strike the fine balance between being protected and overreacting is often the engine to more serious pathologies. The failure to resolve inflammatory immune responses results in chronic inflammatory airway diseases. Chronic airway inflammation is a general feature of chronic obstructive pulmonary disease (COPD) which affects ~5% of the global population and is the fourth leading cause of death worldwide. COPD was estimated by the CDC in 2010 to cost the US more than $32 billion annually, with a projection to grow to an annual cost of $49 billion by 2020. Chronic airway inflammation is also a critical issue in certain types of asthma, cystic fibrosis (CF), and bronchopulmonary dysplasia (BPD). 

Current strategies to treat these chronic pathologies focus in large part on inhibiting pro-inflammatory pathways in the lung. For example, targets for the treatment of various forms of severe asthma and allergy that are currently drugged include: IgE for allergic asthma, three different epitopes of IL-5 (here, here and here) for eosinophilic inflammation, and the receptor of IL-4 which blocks both IL-4 and IL-13 pathways. It should be noted that a number of these drugs (here and here) were candidates to help curb the immune response triggered by the COVID-19 infection, but none of them have proven to be efficacious.

Some encouraging novel efforts to treat chronic airway inflammation are targeting alternative and more recently discovered avenues such as the JAK pathway. As mentioned above, the challenge to such strategies is to effectively shut down part of the immune response without leaving the patients vulnerable to opportunistic pathogens or crippled by side effects. Due to different profiles of inflammatory responses, however, no single strategy has proven itself to be effective for all people, and response rates for existing therapies have generally been poor

Increasing specificity without sacrificing efficacy is a difficult path to walk. To this end, Digitalis is proud to have launched Alcea Therapeutics which is focusing on controlling regulatory T cell (Treg) dysfunction during inflammation. Alcea is built on the belief that the ability to identify and target specific populations of Tregs will hold the key to greater efficacy and specificity in treating severe asthma, not by treating symptoms but by resetting a healthy balance in specific immune systems. More soon!

On this hopeful note, everyone at Digitalis wishes you a safe and healthy end to 2020 (at last) and a much happier New Year.

– Jonathan Friedlander, PhD & Geoffrey W. Smith