Respiratory diseases are among the leading causes of morbidity and mortality worldwide, affecting millions of people of all ages and backgrounds. They can be caused by various factors, such as infections, genetic mutations, environmental exposures, or immune dysregulation. The development of effective and safe therapeutics and vaccines for respiratory diseases is a major challenge and an unmet medical need. Conventional approaches, such as small molecules, biologics, or gene therapy, have limitations, such as low bioavailability, high immunogenicity, or off-target effects. mRNA therapeutics are a new class of drugs that use synthetic mRNA molecules to deliver genetic information to the cells, instructing them to produce therapeutic proteins in situ. mRNA therapeutics have several advantages over conventional approaches, such as direct production of therapeutic proteins, easy design and modification, and low immunogenicity. mRNA therapeutics can be used to encode various types of proteins, such as antibodies, antigens, enzymes, or regulators, to achieve different therapeutic goals, such as neutralizing pathogens, eliciting immunity, correcting genetic defects, or modulating inflammation.
mRNA therapeutics offer a novel and promising strategy to treat or prevent lung infections by encoding therapeutic proteins that can neutralize or eliminate the pathogens. mRNA therapeutics can be classified into three categories based on the type of protein they encode—neutralizing antibodies, antigens, or Cas13.
Neutralizing antibodies are proteins that bind to specific epitopes on the surface of the pathogens and block their entry, replication, or spread. mRNA encoding neutralizing antibodies can be delivered to the lungs to provide passive immunity against the pathogens. For example, mRNA-LNP encoding an antibody against the RSV F protein was shown to protect mice from RSV infection and reduce viral load and lung inflammation. Similarly, mRNA-LNP encoding an antibody against the SARS-CoV-2 spike protein was shown to protect hamsters from SARS-CoV-2 infection and reduce viral load and lung pathology.
Antigens are proteins that stimulate the immune system to produce antibodies and T cells against pathogens. mRNA encoding antigens can be delivered to the lungs to induce active immunity against the pathogens. For example, mRNA-LNP encoding the RSV F protein was shown to elicit robust and durable antibody and T cell responses in mice and protect them from RSV challenge. Similarly, mRNA-LNP encoding the SARS-CoV-2 spike protein was shown to elicit potent and long-lasting antibody and T cell responses in mice, monkeys, and humans and protect them from the SARS-CoV-2 challenge.
Cas13 is a CRISPR-associated protein that can cleave RNA molecules in a sequence-specific manner. mRNA encoding Cas13 can be delivered to the lungs to edit or degrade the RNA of the pathogens. For example, mRNA-LNP encoding Cas13 and a guide RNA targeting the influenza A virus were shown to reduce viral load and lung damage in mice. Similarly, mRNA-LNP encoding Cas13 and a guide RNA targeting the SARS-CoV-2 genome were shown to inhibit viral replication and reduce viral load in cell culture.
mRNA therapeutics offer a novel and promising strategy to treat inflammatory diseases by encoding regulatory proteins that can modulate or suppress the inflammatory response. mRNA therapeutics for inflammatory diseases can be classified into two categories based on the type of protein they encode: (1) cytokines or chemokines, or (2) immune checkpoints or co-stimulators.
Cytokines, or chemokines, are proteins that mediate the communication and activation of immune cells. mRNA encoding cytokines or chemokines can be delivered to the lungs to enhance or inhibit the immune response, depending on the type and context of the inflammation. For example, mRNA-LNP encoding interleukin-10 (IL-10), an anti-inflammatory cytokine, was shown to reduce lung inflammation and airway hyperresponsiveness in a mouse model of asthma. Similarly, mRNA-LNP encoding CCL2, a chemokine that recruits monocytes and macrophages, was shown to attenuate lung fibrosis and inflammation in a mouse model of pulmonary fibrosis.
Immune checkpoints or co-stimulators are proteins that regulate the activation or inhibition of immune cells. mRNA encoding immune checkpoints or co-stimulators can be delivered to the lungs to modulate the balance between immune activation and tolerance, and to prevent or treat autoimmune diseases. For example, mRNA-LNP encoding programmed death-ligand 1 (PD-L1), an immune checkpoint that inhibits T cell activation, was shown to prevent the development of autoimmune diabetes in a mouse model of type 1 diabetes. Similarly, mRNA-LNP encoding CD40 ligand (CD40L), a co-stimulator that activates antigen-presenting cells, was shown to enhance the efficacy of a DNA vaccine against tuberculosis in a mouse model of pulmonary infection.
Genetic disorders are caused by mutations or deletions in the DNA that impair the expression or function of certain proteins. These proteins are often involved in essential metabolic pathways, and their deficiency or dysfunction can lead to various symptoms and complications. Some of the common genetic disorders affecting the lungs include cystic fibrosis, alpha-1 antitrypsin deficiency, and pulmonary hypertension. These disorders have limited or no effective treatments and often require lifelong management or transplantation.
mRNA therapeutics offer a novel and promising strategy to treat genetic disorders by encoding functional proteins that can correct or compensate for the genetic defects. mRNA therapeutics can be classified into two categories based on the type of protein they encode: (1) enzymes or transporters, or (2) receptors or regulators.
Enzymes, or transporters, are proteins that catalyze or facilitate biochemical reactions or the transport of molecules. mRNA encoding enzymes or transporters can be delivered to the lungs to restore normal metabolic function or balance. For example, mRNA-LNP encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein was shown to improve the chloride transport and hydration of the airway surface liquid in cystic fibrosis mice. Similarly, mRNA-LNP encoding the alpha-1 antitrypsin (AAT) protein was shown to increase the serum and lung levels of AAT and reduce the elastase activity and inflammation in AAT-deficient mice.
Receptors, or regulators, are proteins that bind to ligands or signals and modulate the cellular response or gene expression. mRNA encoding receptors or regulators can be delivered to the lungs to modulate the signaling pathways or transcription factors involved in the pathogenesis of the disorder. For example, mRNA-LNP encoding the bone morphogenetic protein receptor 2 (BMPR2) protein was shown to enhance BMP signaling and reverse pulmonary vascular remodeling and hypertension in BMPR2-deficient rats.
Respiratory diseases are caused by various pathogens, such as viruses, bacteria, or fungi, that invade and damage the respiratory tract. They can result in symptoms such as cough, fever, shortness of breath, and pneumonia. Some of the common respiratory diseases include COVID-19, RSV, influenza, and pneumococcal infection. These diseases pose a serious threat to public health, especially for vulnerable populations such as children, the elderly, and immunocompromised individuals. Current vaccines for respiratory diseases are mainly based on inactivated or attenuated pathogens, subunit proteins, or polysaccharides, but they have limitations, such as low immunogenicity, high production costs, or limited protection.
mRNA vaccines offer a novel and promising strategy to prevent respiratory diseases by encoding viral or bacterial antigens that can elicit protective immunity. mRNA vaccines have several advantages over conventional vaccines, such as high immunogenicity, easy design and modification, and low production cost. mRNA vaccines for respiratory diseases can be classified into structural proteins and non-structural proteins based on the type of antigen they encode.
Structural proteins are proteins that form the surface or the core of the pathogens and are responsible for binding to host cells or eliciting neutralizing antibodies. mRNA encoding structural proteins can be delivered to the lungs to induce humoral and cellular immunity against the pathogens. For example, mRNA-LNP encoding the SARS-CoV-2 spike protein was shown to induce potent and long-lasting antibody and T cell responses in mice, monkeys, and humans and protect them from the SARS-CoV-2 challenge. Similarly, mRNA-LNP encoding the RSV F protein was shown to induce robust and durable antibody and T cell responses in mice and protect them from RSV challenge.
Non-structural proteins are proteins that are involved in the replication or pathogenesis of the pathogens and are responsible for modulating the host immune response or enhancing vaccine efficacy. mRNA encoding non-structural proteins can be delivered to the lungs to induce innate and adaptive immunity against the pathogens. For example, mRNA-LNP encoding the influenza A virus nucleoprotein was shown to induce cross-protective immunity against different strains of influenza A virus in mice. Similarly, mRNA-LNP encoding pneumolysin, a toxin secreted by Streptococcus pneumoniae, was shown to enhance the immunogenicity and protection of a polysaccharide-based vaccine against pneumococcal infection in mice.
In summary, mRNA therapeutics have shown great potential to treat or prevent various respiratory diseases. mRNA therapeutics have several advantages over conventional approaches, such as direct production of therapeutic proteins, easy design and modification, and low immunogenicity. mRNA therapeutics can encode various types of proteins, such as antibodies, antigens, enzymes, or regulators, to achieve different therapeutic goals, such as neutralizing pathogens, eliciting immunity, correcting genetic defects, or modulating inflammation. However, there are still some limitations and gaps that need to be addressed before mRNA therapeutics can be widely applied in the clinic. Therefore, more research and innovation are needed to overcome these challenges and to explore new opportunities and applications of mRNA therapeutics for respiratory diseases.
