Introduction:
The liver plays a vital role in maintaining homeostasis by enhancing detoxification and the metabolism of lipids and proteins. Toxin accumulation, organ damage, and the development of pathological conditions are all consequences of liver dysfunction. Gene mutations cause a variety of liver diseases. Liver transplantation was thought to be the only therapeutic modality for liver diseases. Moreover, liver transplantation has several drawbacks, including a scarcity of liver donors and immune rejection. The development of gene editing methods has made it possible to repair pathological mutations. As a result, gene editing technology will eventually replace liver transplantation as a treatment strategy for liver diseases.
About 30 years ago, the first successful human gene treatment was reported. Peripheral blood T lymphocytes transduced with an ADA-encoding retrovirus have been employed in treating patients with adenosine deaminase (ADA) deficiency. This investigation revealed the benefits of gene therapy and its therapeutic involvement in genetic diseases such as hereditary liver diseases. A single gene mutation causes over 100 different types of liver diseases. As a result, gene therapy may be a suitable option for liver transplantation to treat these disorders.
Many distinct genome editing platforms, like meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered regularly interspaced short palindromic repeat (CRISPR)-associated nucleases, have emerged in recent years. These have profoundly revolutionized targeted genomic manipulation, opening up previously unimagined possibilities for research and therapeutic applications, such as infectious diseases. The necessity for nucleases that produce double-strand breaks (DSBs) that activate non-homologous end joining (NHEJ) as a process of DNA (deoxyribonucleic acid) repair actually results in random insertions or deletions (indels) at the site of cleavage is the primary feature of these approaches. Homology-directed repair (HDR) can substitute the DNA to the cleavage point if a homologous DNA template is nearby.
What Is Gene Editing in Chronic Liver Diseases?
Effect of Gene Editing on Alpha-1 Antitrypsin Deficiency (AATD):
AATD is an autosomal recessive metabolic disease and one of the most prevalent liver disorders. The disease is caused by the c.1096G>A mutation in SERPINA1, which codes for alpha-1 antitrypsin (AAT). The mutation results in Glu342Lys substitution (also known as Z mutation), which reduces AAT levels by 70 to 85 percent. AATD is linked to hepatic dysfunction, which typically manifests as high serum aminotransferase levels, hyperbilirubinemia, jaundice, and the most general clinical manifestations of chronic obstructive pulmonary disease (COPD). AATD-related lung disease is treated with AAT injections, whereas hepatic disease frequently necessitates liver transplantation. A dual recombinant adeno-associated virus (rAAV) system was given to patients with AAT to repair the E342K substitution via HDR. Moreover, the rate of gene collection was lower (five percent) than expected.
How Does Gene Editing Affect Hemophilia?
Hemophilia A (HA) or hemophilia B (HB) is an X-linked bleeding disorder triggered by mutations in the F8 gene encoding coagulation factor VIII (FVIII) or the F9 gene encoding coagulation factor IX (FIX). Genetic mutations cause HA in the F8 locus, such as insertions, inversions, point mutations, and large deletions. The inversion breaks in intron 1 or 22 and upstream of associated similar sequences of the F8 gene can cause nearly 50 percent of severe HA cases.
How Does Gene Editing Affect Phenylketonuria (PKU)?
Mutations in phenylalanine hydroxylase (PAH), which encodes phenylalanine hydroxylase, cause phenylketonuria (PKU). PAH controls the catalysis of phenylalanine hydroxylation in tyrosine. The decrease in the activity of PAH causes an increase in phenylalanine in the blood, which produces neurotoxic effects. If left untreated, PKU can inhibit cognitive development and cause other symptoms such as autism, eczematous rashes (skin rashes), motor deficits, and seizures. Dietary phenylalanine restriction is the primary treatment for PKU. Patients frequently show only minor improvements. Other possible strategies include using tetrahydrobiopterin to stimulate enzyme activity, which includes PAH, or using antagonists of phenylalanine uptake at the blood-brain barrier. To overcome the poor outcomes of current treatments, an adjuvant therapy method to repair mutations in PAH is required.
How Does Gene Editing Affect Wilson's Syndrome?
WD is a rare genetic disease induced by loss-of-function mutations in the gene encoding the copper-transporting P-type ATPase (ATP7B). ATP7B is a gene that encodes a protein that transports copper from the liver. As a result, WD is distinguished by increased accumulation of hepatic copper, which causes systemic toxicity. WD leads to liver disease, brain injury, and death if left untreated. Patients frequently develop liver dysfunction, fatigue, and discoloration of the skin. WD is presently treated with liver transplantation, which recovers biliary copper excretion and normalizes copper levels in the blood but necessitates lifelong immunosuppression.
How Does Gene Editing Affect Ornithine Transcarbamylase (OTC) Deficiency?
OTC (ornithine transcarbamylase) deficiency is a rare X-linked genetic disorder characterized by the absence of the OTC enzyme, which plays a role in nitrogen elimination, resulting in buildup of ammonia (hyperammonemia) via the urea cycle. The buildup of ammonia caused by the absence of the OTC enzyme moves through the blood to the central nervous system, causing the symptoms associated with OTC deficiency. The disease is treated with ammonia scavengers such as sodium benzoate and dietary protein restriction. In cases of hyperammonemia, liver transplantation is considered.
How Does Gene Editing Affect Tyrosinemia Type 1 (HT1)?
Tyrosinemia type 1 (HT1) is a rare genetic tyrosine catabolism disorder characterized by a loss-of-function mutation in the fumarylacetoacetate hydrolase gene (FAH). FAH deficit promotes the accumulation of fumarylacetoacetate, maleylacetoacetate, and their derivatives, resulting in liver and renal tubular damage of the liver and renal tubules. By hindering hydroxyphenylpyruvate dioxygenase (HPD) in tyrosine catabolism upstream of FAH, nitisinone rescues the pathological phenotype and acute liver injury. HT1 is responsive to gene repair therapy because repaired hepatocytes proliferate optimally in the liver. Repair of FAH mutations and knockout of HPD are the two main genome editing techniques used to manage HT1.
How Does Gene Editing Affect Arginase-1 Deficiency (Argininemia)?
Arginase-1 deficiency is a urea metabolism-related genetic disorder in which the hydrolysis of arginine to urea and ornithine is impaired due to ARG1 mutations. Clinical management of arginase-1 deficiency includes dietary restrictions, therapeutic interventions with nitrogen scavengers, and enzyme replacement therapies equivalent to OTC deficiency management.
Conclusion:
As the liver metabolizes all foreign particles, gene editing components can be readily delivered to the liver intravenously. Traditional gene therapy has long been used to target the liver, demonstrating that it is an ideal organ for these therapies but also that the different outcomes depend on its ability to regenerate, thus diluting episomal transgenes by cell division, particularly in younger patients.
