Asthmatic patients have breathing difficulties when small particulate matter enters their respiratory system; the filtration capacity of their lungs is deteriorated tremendously. One of the most difficult conditions to endure and sustain, asthma affects approximately 30 million people across America. More than 3 million people develop this fatal condition, which is not just severe but also resistant to therapy.
Despite the widespread increase in the number of asthma patients, the therapy has not changed significantly in the past seven decades. Even today, the conventional medications simply treat asthmatic symptoms; they do not address the causes of this disease. A novel pathway is being created to address the allergic condition effectively. With current modes of treatment, asthma symptoms can be relieved effectively, that is, the constricted airways of the patient can be mitigated effectively. Thus, patients can then heave a sigh of relief and breathe comfortably.
In general, patients are administered steroids that effectively combat inflammation. Scientists are of the view that constriction of airways is caused by inflammation in asthma patients, leading to shortness of breath. Most asthmatic patients appear to have been enduring a panic attack, and they are rushed to emergency room. The symptoms, causes, and pathophysiology of asthma have been investigated elaborately for the past 20 years. The best methods would be to elucidate how airway constrictions can be effectively combated with different molecular mechanisms.
Patients suffering from asthma would develop the illness when exposed to exceeding levels of pollutants; these pollutants are specifically known as allergens, which are found in various environmental conditions. The allergens easily enter the alveoli of lungs and instigate a chain reaction through various molecular pathways; these allergens attack lungs and lead to the development of asthmatic condition. Immune cells are activated by allergens, which are transported to lungs. A strong IgE antibody response is elicited by these cells. Cytokines are secreted by immune cells, which act as mediators to immune cells.
In particular, cytokines IL-4 and IL-13 are easily observed in asthmatic patients. The transcription factor STAT6 is the molecule that is activated by these cytokines; the expression of several genes can be provoked by this molecule. The airways would be constricted easily, and this leads to shortness of breath in asthmatic patients. In the laboratory, mice were modified genetically in such a way that they lacked STAT6. These mice also lacked responses elicited by the interaction between IL-4/IL-13/STAT6; these mice became almost resistant to asthma.
Asthma attack is mediated by a series of immune responses; the transcription factor STAT6 would usually be at the epicenter of immune responses. Researchers devised ways in which STAT6 activation could be blocked effectively. For the activation of STAT6, the immune cells would be bound to IL-4 and IL-13; these molecules are known as receptors. A subunit IL4R-alpha would be shared by these receptors, activating STAT6. Several research studies have been conducted in our laboratory, illustrating that STAT6 can be activated by a set of receptors that are completely different in nature. A small molecule would be developed in such a way that it would directly suppress the activity of STAT6.
The main objective of researchers is to design a small molecule that specifically targets STAT6; the transcription factor STAT6 is always present inside cells of lungs. The strategy would be to suppress several unwanted side-effects. Researchers have succeeded in synthesizing the small molecule PM-43I through chemical pathway; the allergic reaction dependent on STAT6 would be suppressed by this small molecule PM-43I.
To combat the pre-existing allergic disease in mice, a minimum dose 0.25 μg/kg of PM-43I was administered. Furthermore, the kidneys could easily flush out PM-43I; no long-term toxicity would be observed in these patients. This indicates that PM-43I was a very effective small molecule, which could be considered as a therapeutic drug in the treatment of asthma.
Further clinical trials must be conducted to introduce PM-43I as an asthma drug. Under such conditions, steroid treatment would not be required by the patient for survival. Most conventional asthmatic drugs are steroids, which can drive out inflammation and also elicit immune responses. These responses are nothing but the ability of the human body to fight infection.
These researchers claim that asthma attacks can be combated effectively with the small molecule PM-43I; the mice’s ability to combat pathogens would not be impaired with this small molecule. Presently, the probability of developing pneumonia increases in asthmatic patients as they are prescribed steroids. The immune system is severely compromised by steroids. The pathway that causes asthma is effectively targeted with the small molecule PM-43I; the remaining pathways are uncompromised and the body would be able to effectively fight the illness.
The small molecule PM-43I is promising enough to be solely used for the treatment of asthma. In such cases, steroids would never be required for the treatment of asthma. As a result, patients’ immune system would never be compromised and the patient would be able to fight infections.
Previous studies have reported that IL4R-alpha can be effectively targeted with monoclonal antibodies; moreover, these monoclonal antibodies can also suppress the allergic reaction triggered by STAT6. Nevertheless, the Food and Drug Administration has to yet approve these antibodies. As compared to several larger antibodies, it is advantageous to use small molecule antibodies. Compared to monoclonal antibody, it is easier and less expensive to synthesize small molecules.
Quite a few patients would be either sensitive or intolerant to monoclonal antibodies, which is the conventional mode of treatment. Although the molecule PM-43I is synthesized chemically, it is very small in size; therefore, people may not usually develop sensitivity to these small molecules. Compared to antibodies, small molecule would be more effective in blocking STAT6. Chronic inflammation triggers asthma attacks in patients. The small molecule PM-43I can effectively tackle this chronic inflammation. Thus, the condition would be easily cured by adopting the small molecule approach.