Biological Barriers for Drug Delivery and Development of Innovative Therapeutic Approaches in HIV, Pancreatic Cancer, and Hemophilia A/B

Abstract

Biological barriers remain a major obstacle for the development of innovative therapeutics. Depending on a disease's pathophysiology, the involved tissues, cell populations, and cellular components, drugs often have to overcome several biological barriers to reach their target cells and become effective in a specific cellular compartment. Human biological barriers are incredibly diverse and include multiple layers of protection and obstruction. Importantly, biological barriers are not only found at the organ/tissue level, but also include cellular structures such as the outer plasma membrane, the endolysosomal machinery, and the nuclear envelope. Nowadays, clinicians have access to a broad arsenal of therapeutics ranging from chemically synthesized small molecules, biologicals including recombinant proteins (such as monoclonal antibodies and hormones), nucleic-acid-based therapeutics, and antibody-drug conjugates (ADCs), to modern viral-vector-mediated gene therapy. In the past decade, the therapeutic landscape has been changing rapidly, giving rise to a multitude of innovative therapy approaches. In 2018, the FDA approval of patisiran paved the way for small interfering RNAs (siRNAs) to become a novel class of nucleic-acid-based therapeutics, which-upon effective drug delivery to their target cells-allow to elegantly regulate the post-transcriptional gene expression. The recent approvals of valoctocogene roxaparvovec and etranacogene dezaparvovec for the treatment of hemophilia A and B, respectively, mark the breakthrough of viral-vector-based gene therapy as a new tool to cure disease. A multitude of highly innovative medicines and drug delivery methods including mRNA-based cancer vaccines and exosome-targeted therapy is on the verge of entering the market and changing the treatment landscape for a broad range of conditions. In this review, we provide insights into three different disease entities, which are clinically, scientifically, and socioeconomically impactful and have given rise to many technological advancements: acquired immunodeficiency syndrome (AIDS) as a predominant infectious disease, pancreatic carcinoma as one of the most lethal solid cancers, and hemophilia A/B as a hereditary genetic disorder. Our primary objective is to highlight the overarching principles of biological barriers that can be identified across different disease areas. Our second goal is to showcase which therapeutic approaches designed to cross disease-specific biological barriers have been promising in effectively treating disease. In this context, we will exemplify how the right selection of the drug category and delivery vehicle, mode of administration, and therapeutic target(s) can help overcome various biological barriers to prevent, treat, and cure disease.

Keywords: AAV vector; HIV; HIV microbicide; RNA interference; biological barrier; etranacogene dezaparvovec; hemophilia A and B; pancreatic cancer; tumor microenvironment; valoctocogene roxaparvovec.

Figure 1

Biological barriers forming hurdles for HIV treatment. The success of HIV in establishing a worldwide pandemic is largely attributed to the multitude of biological barriers that HIV harnesses to evade both the host immune system and different treatment approaches. Its genetic heterogeneity, its deep infiltration and paralysis of the host immune system, the viral infection of various cell populations, and viral latency as provirus are major factors that explain why the development of an effective vaccine to eradicate the pandemic remains elusive.

Figure 2

Hallmarks of pancreatic cancer and overview of biological barriers which challenge treatment success. The tumor microenvironment, genetic diversity, and metastatic potential are hallmarks of pancreatic cancer which contribute to the malignancy and treatment resistance of pancreatic cancer. At the same time, by forming a variety of biological barriers, they impede effective treatment.

Figure 3

Biological barriers which challenge AAV-mediated gene therapy. The host immune system, the vector organotropism, and the sustainability of transgene expression are challenging barriers for the successful application of AAV-based gene therapy. Careful transgene and vector design contribute to overcoming these barriers, hence paving the way for the success of gene therapy.