Pharma Focus Europe

Addressing the Unmet Needs in Respiratory Disease Treatment with Inhaled mRNA Medicines

Carsten Rudolph, PhD, co-founder & CEO, Ethris

Progress in mRNA technology has paved the way for the creation of inhaled mRNA medications, offering significant potential to transform the management of respiratory diseases, addressing substantial unmet needs in this field. Yet, the key challenge in applying this technology clinically revolves around finding a delivery system that is not only safe but also effective. This article delves into the prospects and obstacles linked to inhaled mRNA medicines, poised to reshape the paradigm of treating respiratory diseases.

Advancements in medical science have continually pushed the boundaries of what is possible in healthcare. Among the most recent innovations is the development of inhaled mRNA medicines, a groundbreaking approach that holds immense potential for transforming the landscape of respiratory disease treatment. Respiratory diseases, which encompass a wide range of conditions from chronic obstructive pulmonary disease (COPD) to asthma and rare genetic disorders like primary ciliary dyskinesia (PCD), have posed significant challenges to both patients and healthcare providers. These diseases often require complex treatments, and there is a pressing need for therapies that are more effective, less invasive, and tailored to individual patient needs. In this article, we will take a closer look at the opportunities and challenges related to inhaled mRNA medicines, poised to revolutionize the treatment of respiratory disease treatment and address these currently unmet needs.

The Promise of Inhaled mRNA Medicines

mRNA therapeutics offer several significant advantages when compared to other therapeutic approaches, including DNA-based treatments, protein-based drugs, and small molecules. One key advantage of mRNA-based medicines is their modularity, allowing for easy customization through sequence modification. This enables the creation of tailored molecules capable of precisely targeting specific proteins or genes, directly addressing the root causes of diseases, and potentially halting or reversing their progression. The production of mRNA therapeutics is also notably rapid in comparison to the manufacturing of antibodies or protein-based drugs. Additionally, mRNA therapeutics are characterized by their predictable pharmacokinetics and the absence of genomic integration, contributing to their relative safety. This functional versatility makes them suitable for a wide range of applications, including the development of viral vaccines, protein replacement therapies, cancer immunotherapies, and cellular reprogramming.

Research is underway to assess diverse administration routes for enhancing mRNA transport and expression. These include tracheal inhalation, as well as intravenous, intraperitoneal, and intramuscular injections. Inhaled mRNA medicines represent a paradigm shift in the treatment of respiratory diseases. Unlike traditional oral or intravenous medications, which often distribute throughout the entire body, inhaled mRNA medicines offer a localized and targeted approach by delivering therapeutic molecules directly to the lungs.

Another exciting aspect of inhaled mRNA medicines is their potential for sustained therapeutic effects. For example, in the case of patients suffering from primary ciliary dyskinesia (PCD), a comparably short-lived mRNA can have a long-lasting effect due to the pharmacokinetics of the produced protein which is only generated once in the cell's lifetime (approximately 6 weeks). This not only improves patient compliance but also has the potential to reduce the frequency of treatments, making it a more convenient and cost-effective approach.

Inhaled mRNA medicines are versatile in their applications. They can be employed for both acute and chronic lung conditions, offering a wide range of treatment options. Whether it's addressing sudden exacerbations of respiratory diseases or managing long-term conditions, these medicines provide flexibility in patient care, allowing healthcare providers to tailor treatment plans to individual needs.

This precision in drug delivery is a game-changer, as it minimizes systemic side effects and enhances treatment efficacy while reducing adverse reactions.

Navigating the Complex Challenges

While the promise of inhaled mRNA medicines is evident, there are several significant challenges that must be overcome to bring these therapies to fruition in clinical practice. As natural biological molecules, mRNAs are inherently highly unstable and vulnerable to degradation by RNA-cutting ribonuclease enzymes.  Due to their natural biological nature, mRNAs are intrinsically unstable and susceptible to degradation by RNA-cutting ribonuclease enzymes.

One of the most critical challenges, as with all mRNA medicines, is ensuring targeted delivery to lung tissues while minimizing systemic exposure. Achieving this delicate balance is essential to prevent unintended effects of the drug on other organs and systems in the body.

Technical hurdles also exist in the development of inhaled mRNA medicines. Achieving consistent protein expression and developing efficient nebulization methods are ongoing areas of research and development. Lipid nanoparticle (LNP) aggregation is one such challenge that researchers are diligently working to address, especially in the case of inhaled delivery with a nebulizer. These aggregations can hinder the effective delivery of therapeutic mRNA to target cells in the lungs, potentially compromising treatment outcomes and causing an immune reaction against the therapy itself.

Another significant concern in the realm of mRNA-based therapies is immunogenicity. Some existing therapies, including mRNA-based treatments, can provoke excessive immune responses. This can lead to unwanted inflammatory reactions or immune responses against the therapy itself. Managing and mitigating immunogenicity is a paramount consideration in ensuring the safety and effectiveness of inhaled mRNA medicines.

In order to circumvent these shortcomings and enhance their therapeutic potential, mRNA molecules necessitate chemical modification and the implementation of optimized delivery systems, aiming to achieve not only maximum potency and efficient cellular uptake but also to minimize any potential issues related to toxicity and immunogenicity.

Delivering mRNA into human cells is a complex process, demanding specialized delivery systems to shield therapeutic mRNA from degradation and aid its cellular entry. Selecting the appropriate delivery vehicle is crucial, as it needs to minimize immune responses and overcome the challenges posed by systemic or inhalable administration routes, which significantly impact organ distribution and treatment effectiveness.

While mRNA technologies are still undergoing long-term assessments of safety and effectiveness, recent advancements in novel materials and delivery formulations are emerging as effective solutions to improve the overall therapeutic efficiency.

Furthermore, stability is a critical challenge in mRNA manufacturing and its subsequent storage and use. One of the key aspects of the stability challenge in mRNA manufacturing and storage has to do with temperature sensitivity. mRNA is highly sensitive to temperature. Elevated temperatures can lead to the degradation of mRNA molecules, which can pose a challenge not only during the manufacturing process but also during storage and transportation.

Exploring the Vast Applications of Inhaled mRNA Medicines

The potential applications of inhaled mRNA medicines in respiratory disease treatment are vast and promising. In addition to having the potential to treat chronic obstructive pulmonary disease (COPD), they have shown potential in addressing genetic lung conditions, such as primary ciliary dyskinesia (PCD) or certain auto-immune diseases like pulmonary alveolar proteinosis (PAP).

Inhaled mRNA has the potential to address PCD, a rare genetic condition resulting from structural abnormalities or the lack of cilia in the lining of our respiratory tract. When cilia can't perform their function, mucus containing trapped microbes, dust, and other debris cannot be efficiently cleared from the airways, often causing lasting lung damage. In this case, the mRNA therapy would deliver a corrected mRNA, directly to the lungs through inhalation that is designed to produce ciliary proteins in the respiratory tract to restore cilia function.

Inhaled mRNA also has the potential to address PAP, a rare autoimmune condition that leads to breathing difficulties by impairing gas exchange in the lungs. In approximately 90% of cases, the disease is caused by the development of autoantibodies targeting GM-CSF, leading to malfunctioning local macrophages and the accumulation of surfactant, an oily substance, in the lung's small air sacs known as alveoli. Currently, there is no approved curative pharmacotherapy available. Inhalation of recombinant GM-CSF (rGM-CSF) has limited clinical efficacy due to high levels of endogenous anti-GM-CSF antibodies and the potential for further induction of anti-drug-antibody following treatment with recombinant protein. In the case of PAP, an inhaled RNA therapy can be delivered directly to the lung that is designed to restore local macrophage function.

Providing a platform for immunomodulation via mRNA encoding for antibodies or cytokines offers the potential to revolutionize how we manage respiratory infections and conditions like asthma. Infections of the respiratory tract, including Influenza (Flu) and Covid-19 can vary in severity depending on a person’s level of immunity. Inhaled mRNA has the potential to provide anti-viral therapies that activate the body’s innate immune system specifically in the lungs, where the virus enters the body. By targeting the mRNA to the lung, an antiviral defence can be mounted directly in patients’ lungs and can significantly impact the viral infection process. This approach can treat both seasonal and potentially newly emerging respiratory viruses by acting to mount the patient’s own immune defense directly in the lungs, independently of the specific virus.

Another particularly exciting aspect is the potential for personalized medicine in respiratory disease treatment. Inhaled mRNA medicines can be tailored to individual patients, addressing specific genetic mutations or immune system profiles. This level of customization holds great promise for improving treatment outcomes and enhancing the quality of life for patients with respiratory diseases.

A Glimpse into the Future of Inhaled mRNA Medicines

The future of inhaled mRNA medicines is bright, filled with promise, and poised to usher in a transformative era in the field of respiratory disease treatment. Some pioneering companies have made significant strides in the field by developing in-house technologies that not only enhance the delivery of therapeutic payloads to the lungs but also address key challenges that have historically hindered treatment efficacy.

Such advancements include the development of innovative technologies designed to prevent lipid nanoparticle (LNP) aggregation during nebulization, a crucial step in the administration of inhaled mRNA medicines. By preserving the stability of these therapeutic agents during distribution and handling, these technologies ensure that the intended therapeutic effects are maximized.

Through extensive data analysis and research, the field is making significant progress in minimizing off-target delivery to other organs. This precision and efficiency in drug administration are crucial to the success of inhaled mRNA medicines.

Technology is also making great strides in storage and manufacturing.  The success of mRNA therapeutics relies significantly on the stability of th supply chains and manufacturing capabilities. Research is ongoing to develop alternative storage and distribution methods that don't rely on deep freezing. This includes investigating the potential of refrigeration or even room-temperature storage for certain mRNA products. To deliver mRNAs directly to the respiratory tract, new stabilizing technology is now enabling drug candidates with superior thermostability and high resistance to mechanical manipulation for use with a nebuliser. Additionally, companies are working on improving the supply chain for their raw materials as well as excipients. Leaders in this space have already found a way to develop stable and scalable, HPLC-free upstream and downstream manufacturing processes that enable the production of high-quality product candidates for clinical supply.

Another exciting frontier in the world of inhaled mRNA medicines is the integration of advanced technologies like gene editing and CRISPR-Cas9. Researchers are actively exploring the possibility of correcting genetic mutations that underlie certain lung conditions. This groundbreaking approach holds the promise of not merely managing symptoms but potentially offering a cure, a prospect that was once considered beyond reach.

As these advancements continue to evolve, inhaled mRNA medicines are poised to reshape the landscape of respiratory disease treatment, opening doors to an array of possibilities. Inhaled mRNA medicines represent a transformative approach to the treatment of respiratory diseases, offering precision, sustained therapeutic effects, and versatility. These innovative therapies are on the cusp of significantly enhancing the lives of millions of patients worldwide, thereby paving the way for a brand-new era in respiratory healthcare. While there are significant challenges to overcome, the potential benefits are immense, addressing unmet needs in respiratory disease treatment. With continued advancements, we can expect to see these medicines become an integral part of the treatment arsenal for respiratory diseases, ultimately redefining the way we approach and manage these conditions.

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Author Bio

Carsten Rudolph

Carsten Rudolph, Ph.D. is a co-founder of Ethris and the lead inventor of its SNIM® RNA Technology. His deep expertise lies in delivering mRNA specifically to the lungs. He is the inventor of 15 patents/applications and has authored more than 120 scientific publications. Carsten is affiliated with the Dr. von Haunersche Children’s Hospital, part of Ludwig Maximilian University in Munich. He obtained his pharmaceutical degree from the Freie Universität Berlin.

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