Future Perspectives of Oral Delivery of Next Generation Therapies for Treatment of Skin Diseases

Abstract

Gene therapies have conspicuously bloomed in recent years as evidenced by the increasing number of cell-, gene-, and oligo-based approved therapies. These therapies hold great promise for dermatological disorders with high unmet need, for example, epidermolysis bullosa or pachyonychia congenita. Furthermore, the recent clinical success of clustered regularly interspaced short palindromic repeats (CRISPR) for genome editing in humans will undoubtedly contribute to defining a new wave of therapies. Like biologics, naked nucleic acids are denatured inside the gastrointestinal tract and need to be administered via injections. For a treatment to be effective, a sufficient amount of a given regimen needs to reach systemic circulation. Multiple companies are racing to develop novel oral drug delivery approaches to circumvent the proteolytic and acidic milieu of the gastrointestinal tract. In this review, we provide an overview of the evolution of the gene therapy landscape, with a deep focus on gene and oligonucleotide therapies in clinical trials aimed at treating skin diseases. We then examine the progress made in drug delivery, with particular attention on the peptide field and drug-device combinations that deliver macromolecules into the gastrointestinal tract. Such novel devices could potentially be applied to administer other therapeutics including genes and CRISPR-based systems.

Keywords: CRISPR; clinical trials; drug-device combinations; epidermolysis bullosa; gene therapy; oligonucleotides; oral biologics; oral devices; regenerative medicine; skin diseases.

Figure 1

Schematic depicting the most commonly used oligonucleotide modifications. OMe: 2′-O-methyl, MOE: 2′-methoxyethyl, LNA: locked nucleic acid, PS: phosphorothioate, PO: phosphorodiester, PNA: peptide nucleic acid, PMO: phosphorodiamidate morpholino oligomer, GalNAc: N-acetylgalactosamine. * These chemistries are used in single stranded ASOs.

Figure 2

Devices designed to deliver biologics in the gastrointestinal tract. (A) RaniPill™ capsule delivering to the small intestine via a microneedle (Image provided by Rani Therapeutics) [147,148]; (B) SOMA device prototypes aimed to deliver in the stomach wall (Photo credit and copyright: Felice Frankel) [149]; (C) LUMI device unfolded (top) and inside the enteric coated capsule (bottom) (Adapted with permission from [150], Nature Medicine, 2019); (D) Flower-like device for esophageal administration [151]; E BIONDD™ device prototype for stomach delivery (Image credit Anne Lena, provided by Biograil™) [152]; (F) Oral biotherapeutics delivery system (Photo provided by Progenity) [153] and (G) JetCAP™ capsule delivers a needle-free liquid injection into the gut wall (Image provided by Baywind Bioventures) [154,155]; (H) MucoJet^® needle-free system for drug delivery in the oral cavity next to a hypodermic needle (Photo credit: Stephen McNally/UC Berkeley) [156]; and (I) Self-expanding device for small intestine delivery (Photo provided by Epitomee Medical) [157].