By Guillermo “Gil” Marmol, president and chief executive officer, Porosome Therapeutics, Inc.
The landscape of drug discovery has undergone a remarkable transformation propelled by breakthroughs in genomics, gene editing technologies, stem cell biology, patient-derived organoids, cryo-electron microscopy, synthetic biology, and AI-driven small molecule screening. Despite these leaps, a significant challenge persists: Approximately 85% of disease-causing proteins remain elusive and impervious to current therapeutic interventions.
One potential pathway to address this problem is the structure in the cell that constitutes its secretory machinery, the porosome. The porosome was discovered relatively recently — some 30 years ago. It is a cup-shaped multiprotein complex residing in the cell plasma membrane and is a selective doorway that regulates the secretion of intracellular products from the cell. Porosomes enable communication between cells in the body by secreting chemical messages such as neurotransmitters from nerve cells or hormones from endocrine cells such as insulin from beta cells of the endocrine pancreas. These chemical messages are stored in secretory vesicles within the cell.
The porosome is made up of more than 30 proteins, several of which are undruggable. Malfunctions in any one of the porosome proteins can result in secretory defects, leading to a disease. In some cases, more than one porosome protein may be involved in such secretory disorders. Many diseases, including cystic fibrosis, type 1 and type 2 diabetes, neurological disorders like Alzheimer’s disease, immune disorders, and various cancers, result from secretory defects.
During the decades since its discovery, step-by-step research characterized the molecular details of the porosome-mediated cell secretion process. This work has provided greater understanding of the role of the porosome in cell secretion and its potential role in developing innovative therapeutics for multiple diseases. Much as mRNA and gene editing have served as platforms for addressing various diseases, the porosome, too, shows promise as a multi-drug platform that additionally addresses the undruggable problem.
At Porosome Therapeutics, our platform includes a therapy whereby we can reprogram the porosome to address secretory defects. Thus, porosomes with specific dysfunctional proteins in diseased cells of a given tissue can be corrected by reconstituting functional porosomes containing the normal proteins, obtained from healthy cells, into the cell plasma membrane. The proteins in the reconstituted porosome will perform their normal secretory functions. Published research papers have documented the ability to successfully reconstitute the porosome in cells impacted by various diseases.
This demonstrated capability of porosome reconstitution serves as a path forward in addressing the secretory defects caused by undruggable porosome proteins. Small molecules also can target undruggable porosome proteins. Additionally, such small molecules can be precision-targeted using nanobodies to modulate secretory defects, thereby treating a given disease.
Spotlight On Cystic Fibrosis And Type 1 Diabetes
One clear example of a disease addressed by reprogramming the cell’s secretory machinery is cystic fibrosis, which arises from a protein dysfunction stemming from mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). This chloride channel governs mucus viscosity, notably in lung epithelial cells. Current treatments primarily address the malfunctioning CFTR protein.
By introducing a functional CFTR-associated porosome secretory complex into lung epithelial cells affected by cystic fibrosis, a systemic platform approach can rectify the deficiency caused by all nonfunctional CFTR mutations. This approach offers a comprehensive, potentially curative solution for cystic fibrosis treatment. It has the potential to substantially reduce morbidity and mortality and enhance the quality of life for cystic fibrosis patients. This approach could significantly decrease the need for lung transplants among cystic fibrosis patients. ΔF508-CFTR human bronchial organoids, reconstituted with normal porosomes, restore near normal mucin secretion, holding great promise for a pathway to an enduring therapy for cystic fibrosis.
Similarly, a major issue in treating type 1 diabetes (T1D) using beta cells derived from induced pluripotent stem cells (iPSC) is the inability of these beta cells to optimally secrete insulin in response to a glucose challenge. Consequently, a large number of such beta cells derived from iPSC are required for a transplant in the treatment of T1D, posing a significant problem. This can now be overcome by reconstituting insulin-secreting porosomes to the iPSC derived beta cells, prior to their transplant in patients. This would be a combination therapy that would bring together two important therapeutic approaches.
Since the porosome is the cell’s secretory apparatus and is part of the cell, little immune response and cytotoxicity is expected from its reconstitution therapy, thereby diminishing side effects.
Patient-Centric Approach And Collaboration
The platform has successfully achieved functional reconstitution of the porosome complex both in a lipid membrane and in live cells, therefore offering significant promise for therapeutic interventions, high-throughput screening (HTS), and the capability to modulate the function of undruggable targets. Similarly, tissue-specific porosome-targeted therapy has the potential to revolutionize medicine by enabling the creation of an unprecedented variety of medicines tailored to a wide spectrum of secretory disorders that cause different diseases.
Development of tissue-specific medicines targeted to porosomes not only advances therapeutic precision but also significantly elevates drug safety. Targeted toward the porosome, these medicines aim to effectively mitigate toxicity, minimize associated side effects, and mitigate various risks across the entire spectrum of drugs in treating secretory disorders.
At Porosome Therapeutics, we believe that a patient-centric approach means making our therapy as broadly available and as easy to access as possible. One important element is the fact that we expect that our therapeutic approach will prove equally effective against all mutations of cystic fibrosis disease. There are approximately 2,000 mutations of cystic fibrosis and existing therapeutic approaches focus on the ΔF508 CFTR mutation, which has the largest number of patients. Many more patients will be able to benefit from our approach, including those that suffer from mutations that are uncommon and impact a relatively small population. In addition, it is estimated 10 million Americans are asymptomatic carriers of at least one CFTR mutation. These Americans may suffer from diseases caused by the mutation they carry.
A question that comes up in the design of human trials is which participants will be incorporated. Porosome Therapeutics’ answer to this important question is that we are not limiting potential trial participants, because we firmly believe that our therapy will be effective in helping patients in all phases of cystic fibrosis disease. Demonstrating in our trial the broad efficacy of our treatment will create the opportunity to treat the entire cystic fibrosis population.
In addition, we believe the delivery of our drug can be achieved with a standard inhaler much like an asthma inhaler. Additional work will be required to define the final protocol, including frequency of application, but we are confident in the simplicity of application for our drug.
To continue to move healthcare forward, it is essential to anchor drug development and therapies with well vetted science that is patient-centric. It is important to prioritize this through continued research and development programs achieved through close collaboration with leading researchers and experts in the field. It is as important to do the basic research as it is to work on patient-friendly delivery approaches and to work closely with those performing clinical trials.
About the Author:
Guillermo “Gil” Marmol is president and CEO of Porosome Therapeutics, Inc., a Boston-based biotechnology company. Marmol applies his broad and unique strategic planning, development, and operations experience to bring groundbreaking science and technology to market to treat previously intractable and undruggable conditions, with a patient-centric focus. Marmol served as a director (senior partner) of McKinsey & Company. There, he assisted several high-performance organizations in the formulation and execution of growth strategies. His work in organizational design has been recognized in a variety of publications including the Wall Street Journal. Marmol has a B.A. in engineering and applied physics, magna cum laude, from Harvard College, and an MBA with distinction from Harvard Business School.