Gene Therapy for Liver Disease

The liver produces bile, eliminates toxins, stores nutrients, and is pivotal in the metabolism of proteins, fats, and carbohydrates. Famed for its regenerative capacities, it can still be irreparably damaged. Common culprits include viral infections, toxins, and metabolic disorders. These catalysts can outpace the its powers of self-repair (Boyer, 2016).

Worldwide, liver disease kills two million people a year. Deaths are chiefly due to complications from cancer and cirrhosis. The triumvirate of cirrhosis’s common causes alcohol, fatty liver, and viral hepatitis (Devarbhavi, 2023).

Although liver disease may be reversible in its early stages, more serious cases can only be addressed with a transplant — which carries its own set of risks. A transplant is not a certain cure. Although it can greatly improve long-term survival and quality of life, total remission of symptoms is rare. There can be complications, and it is not always a permanent solution (VanHuis, 2019).

Non-alcoholic fatty liver disease (NAFLD) is becoming more prevalent. It is currently difficult to diagnose, and exactly how it begins is complicated. However, it is gradually becoming the primary form of chronic liver disease in adults and children, and soon could become the major reason for transplants (Neuschwander-Tetri, 2017).

New therapeutic approaches are desperately needed. As with many currently “incurable” conditions, gene therapy gives hope.

As it does elsewhere, telomere shortening — one of the hallmarks of aging — limits cell replication, contributing to fibrosis and, eventually, cirrhosis. Telomere shortening is a risk factor for chronic liver disease and hepatocellular carcinoma. Mutations affecting telomerase and other components of the telomere system can lead to chromosomal instability and cancer (Carulli, 2014 ).

Telomere dysfunction is observed in NAFLD, where shorter telomeres are linked to fibrosis. Oxidative and inflammatory stress are thought to accelerate telomere shortening in NAFLD, potentially serving as a predictor for disease progression (Shin, 2021).

Shorter leukocyte telomere length (LTL) is associated with increased fibrosis in NAFLD and non-alcoholic steatohepatitis (NASH). LTL may serve as a biomarker for predicting disease progression. Patents with hereditary telomere disorders often have elevated liver enzymes, steatohepatitis, and cirrhosis (Kapuria, 2019).

Telomerase gene therapy holds preventative and therapeutic promise, but it is not the only gene therapy that could help.

There is a positive correlation between circulating α-Klotho levels and adult NAFLD. Low Klotho levels are linked to NAFLD, especially among women and young people. Klotho, known for its role in kidney health, appears to protect against NAFLD by mitigating oxidative stress, inflammation, and fibrosis — all processes associated with the aging process (Chi, 2023).

A variation in the β-Klotho gene is associated with liver damage in children with NAFLD; it’s also linked to inflammation. The variation results in reduced Klotho expression, which may inflict damage by promoting the expression of inflammatory and lipotoxic genes. Researchers concluded that Klotho may protect against inflammation and lipotoxicity (Dongiovanni, 2020).

Klotho is a defense against alcohol-induced cirrhosis. Elevated levels here, as they are in sepsis and cancer, probably attempts to dampen inflammation (Martín-González, 2019).

PGC-1α is another promising candidate. It encourages the creation of new mitochondria, the “powerplants” of our cells. Any machine can become overworked. If it goes on for too long, it breaks down. When new mitochondria are created, they spread the burden of energy production.

Having reduced and dysfunctional mitochondria is associated with fatty liver disease. Scientists looked to see how increasing PGC-1α in liver cells would change the way cells process fats. Specifically, they wanted to know if PGC-1α would lead to a more efficient conversion of lipids into energy — and less fat in the liver.

Liver cells with more PGC-1α had higher levels of mitochondrial markers and catalyzed fats more efficiently. These cells also stored and released fewer fats compared to normal cells. PGC-1α enhanced cells were better protected against fat buildup when exposed to excess fats overnight (Morris, 2012).

When PGC-1α was increased in live rats, their livers showed enhanced lipid metabolism thanks to improved mitochondrial function, resulting in less fat stored in the liver and fewer lipids in the bloodstream.

Researchers concluded that raising PGC-1α in liver cells fosters mitochondrial function, resulting in better fat breakdown and less fat storage and secretion in the lab and in living animals (Morris, 2012).

A separate study found that mice on a high-fat diet had decreased liver PGC1-α. However, mice with high PGC1-α levels had better mitochondrial function and accelerated lipid metabolism. This leads to less steatosis (fat accumulation) and improved insulin sensitivity (Wan, 2020).

Bolstering PGC1-α in the liver helps reduce liver steatosis and improves insulin sensitivity, suggesting targeting PGC1-α might be an effective treatment for fatty liver diseases (Wan, 2020).

To optimize Klotho and PGC1-α for the best outcome in patients, a better delivery vector is needed. BioViva’s CMV delivery platform lets gene therapy tackle complex diseases.

Currently “incurable” patients are rarely given the opportunity to try therapeutics that could save their lives.

Best Choice Medicine provides a way for us to make a difference by advocating for life-saving therapies to become available to the millions of patients suffering from liver diseases and other potentially terminal conditions.

References and Suggested Reading

Boyer, Thomas D., and Keith D. Lindor. Zakim and Boyer’s hepatology: A textbook of liver disease e-book. Elsevier Health Sciences, 2016.

Carulli L, Anzivino C. Telomere and telomerase in chronic liver disease and hepatocarcinoma. World J Gastroenterol. 2014 May 28;20(20):6287–92. doi: 10.3748/wjg.v20.i20.6287. PMID: 24876749; PMCID: PMC4033466.

Chi Z, Teng Y, Liu Y, Gao L, Yang J, Zhang Z. Association between klotho and non-alcoholic fatty liver disease and liver fibrosis based on the NHANES 2007–2016. Ann Hepatol. 2023 Sep-Oct;28(5):101125. doi: 10.1016/j.aohep.2023.101125. Epub 2023 Jun 5. PMID: 37286168.

Devarbhavi H, Asrani SK, Arab JP, Nartey YA, Pose E, Kamath PS. Global burden of liver disease: 2023 update. J Hepatol. 2023 Aug;79(2):516–537. doi: 10.1016/j.jhep.2023.03.017. Epub 2023 Mar 27. PMID: 36990226.

Dongiovanni P, Crudele A, Panera N, Romito I, Meroni M, De Stefanis C, Palma A, Comparcola D, Fracanzani AL, Miele L, Valenti L, Nobili V, Alisi A. β-Klotho gene variation is associated with liver damage in children with NAFLD. J Hepatol. 2020 Mar;72(3):411–419. doi: 10.1016/j.jhep.2019.10.011. Epub 2019 Oct 23. PMID: 31655133.

Kapuria, Devika, et al. “The spectrum of hepatic involvement in patients with telomere disease.” Hepatology 69.6 (2019): 2579–2585.

Martín-González C, González-Reimers E, Quintero-Platt G, Martínez-Riera A, Santolaria-Fernández F. Soluble α-Klotho in Liver Cirrhosis and Alcoholism. Alcohol Alcohol. 2019 May 1;54(3):204–208. doi: 10.1093/alcalc/agz019. PMID: 30860544.

Morris EM, Meers GM, Booth FW, Fritsche KL, Hardin CD, Thyfault JP, Ibdah JA. PGC-1α overexpression results in increased hepatic fatty acid oxidation with reduced triacylglycerol accumulation and secretion. Am J Physiol Gastrointest Liver Physiol. 2012 Oct 15;303(8)
. doi: 10.1152/ajpgi.00169.2012. Epub 2012 Aug 16. PMID: 22899824; PMCID: PMC3469696.

Neuschwander-Tetri BA. Non-alcoholic fatty liver disease. BMC Med. 2017 Feb 28;15(1):45. doi: 10.1186/s12916–017–0806–8. PMID: 28241825; PMCID: PMC5330146.

Shin, Hee Kyung, et al. “Association between telomere length and hepatic fibrosis in non-alcoholic fatty liver disease.” Scientific Reports 11.1 (2021): 18004.

VanHuis, Adam M.D.1; Loy, Veronica D.O.*,2. Myth: Liver Transplant Provides a Cure for Liver Disease. Clinical Liver Disease 13(6)
154–157, June 2019. | DOI: 10.1002/cld.770

Wan X, Zhu X, Wang H, Feng Y, Zhou W, Liu P, Shen W,

Zhang L, Liu L, Li T, Diao D, Yang F, Zhao Q, Chen L, Ren J, Yan S, Li J, Yu C, Ju Z. PGC1α protects against hepatic steatosis and insulin resistance via enhancing IL10-mediated anti-inflammatory response. FASEB J. 2020 Aug;34(8):10751–10761. doi: 10.1096/fj.201902476R. Epub 2020 Jul 7. PMID: 32633848.

Wojcicki, Janet M., et al. “Shorter leukocyte telomere length protects against NAFLD progression in children.” Scientific reports 13.1 (2023): 5446.