Optimized Biliary Hydrodynamic Injection via Endoscopic Retrograde Cholangiopancreatography for Macromolecule Delivery into the Liver

Unmet Need

The liver is a critical organ that performs more than 500 physiological functions in the human body including maintenance of metabolic homeostasis, digestion of drugs & hormones, and secretion of essential proteins. Unfortunately, the liver is susceptible to a wide variety of diseases that generally result from viral infection, inheritance of deleterious genetic mutations, and exposure to toxic compounds (poisons, pollution, drugs, alcohol, etc.). Genetic liver disorders – including Alpha-1-antitrypsin deficiency (AAT deficiency), Wilson’s Disease, and Hemophilia – have limited treatment options and incur significant morbidity & mortality. Standard-of-care treatments for such genetic liver diseases typically involve protein replacement therapies that compensate for the loss of a functional protein due to an inherited mutation. However, these treatments require patients to take weekly or daily doses of various drugs throughout their lifetime. 

This problem has led to the development of gene therapies, which are intended to cure or significantly improve clinical outcomes for patients with genetic liver disorders by delivering a small number of doses that are effective over long periods of time. Many emerging gene therapies leverage viral vectors to introduce a gene to organs, which can then produce therapeutic levels of a protein for months or years. Nevertheless, viral gene therapies are limited by (1) reduced efficacy due to patient immune responses and technical constraints, (2) prohibitively high cost of manufacturing at scale, (3) and regulatory challenges related to adverse side effects & opaque quality control standards. As such, there is a need treatments for genetic liver disorders that provide a sustained benefit while avoiding many of the challenges associated with viral gene therapies.

Technology Overview

Inventors at Johns Hopkins have developed a method for delivering nucleic acids and/or proteins into liver cells (hepatocytes) through hydrodynamic injection via a surgical procedure called endoscopic retrograde cholangiopancreatography (ERCP). This invention can be leveraged as a non-viral gene therapy to treat a wide array of genetic liver disorders.

Stage of Development

The inventors have conducted an in vivo proof-of-principal study in pig models. The technique used the same clinical tools as are used in human patients.

Publications

Manuscript stage