Confronting a Silent Epidemic: Gene Therapy and COPD

Debilitating, deadly, and tragically overlooked, Chronic Obstructive Pulmonary Disease (COPD) is the seventh cause of poor health, and the third leading cause of death in the world (WHO, 2024).

Characterized by blocked airflow and often the result of respiratory irritants like cigarette smoke, COPD contributes to many other health issues. Symptom control is the current standard of care, as it is currently incurable.

However, gene therapy again gives hope.

Potential therapeutic targets should be familiar to long-time readers: follistatin, telomerase, and Klotho. All three target the aging process, and so are promising candidates for preventing, treating, and even reversing an array of health conditions.

Telomeres and Telomerase in COPD

Telomeres shorten with age, and critically short telomeres contribute to cellular senescence and death (Shammas, 2011).

There are links between telomere length, lung hyperinflation, extrapulmonary affection, and pulmonary gas exchange in patients with COPD. The cohort was followed for ten years; the risk for all-cause mortality rose with telomere shortening (Córdoba-Lanús, 2021).

Telomerase, an enzyme that lengthens telomeres, appears to predispose people to early onset of severe forms of emphysema and COPD when it malfunctions (Stanley, 2016).

Lest any doubts linger, a large scale study exploring the relationship between telomere length, lung function, respiratory disease found “highly significant positive associations between telomere length and lung function.”

People with COPD and asthma have shorter telomeres. The researchers concluded that the broad study provided evidence that premature aging (due to shortened telomeres) is involved in the pathophysiology of both (Albrecht, 2014).

Follistatin and COPD

Follistatin is best known as a myostatin inhibitor. By blocking myostatin, it helps us build muscle. Lean body mass protects us from a score of issues. There is a budding but fascinating literature on its relevance to respiratory disease.

A study on bleomycin (BLM)-treated rat lungs found that activins, members of the transforming growth factor beta (TGF-β), infiltrated the lungs causing structural damage. When follistatin was administered, invasive cells were reduced. By the seventh day, lung damage was measurably mitigated

By day 28 lung fibrosis was attenuated (reduced and weakened). The researchers concluded that follistatin can treat BLM-induced fibrosis and acute lung injury (Aoki, 2005).

Follistatin inhibits activin

Activin-A is increased in patients with COPD, compared to healthy non-smokers. The same is true for mice (and mouse models), suggesting high activin-A and low follistatin levels contribute to COPD and cigarette smoke-induced inflammation. Mice treated with follistatin saw their smoke-induced inflammatory cells attenuated (Verhamme, 2014).

A common comorbidity of COPD is pulmonary hypertension (PH), characterized by abnormal cellular growth in the pulmonary arteries, leading to high blood pressure in the lungs and cardiovascular problems.

Both follistatin and Activin-A are elevated in PH patients. Researchers found mice with reduced follistatin fared poorly, while administering follistatin allayed the condition (Zhang, 2017).

While more research is needed, activin-a inhibition, through follistatin or another therapuetic protein, could be massively helpful.

Klotho in COPD

Klotho, arguably the most versatile anti-aging protein known, protects cells from inflammation and damage. In a study of 59 patients, it was most abundant in nonsmokers, reduced in healthy smokers, and markedly scant in those with COPD.

Expression is reduced by 65% in the lungs of COPD patients, showing that Klotho deficiency may be another part of the genesis and progression of COPD (Gao, 2015).

The Road Ahead

To harness gene therapy for COPD and other “incurable” conditions, we push for patient access. This is what Best Choice Medicine is doing now.

Sign the petition and spread the word!

The other side is technical. To attack complex disorders like COPD from all relevant angles, we need large and robust gene delivery systems like BioViva’s CMV platform.

References and Works Cited

Albrecht E, Sillanpää E, Karrasch S, Alves AC, Codd V, Hovatta I, Buxton JL, Nelson CP, Broer L, Hägg S, Mangino M, Willemsen G, Surakka I, Ferreira MA, Amin N, Oostra BA, Bäckmand HM, Telomere length in circulating leukocytes is associated with lung function and disease. Eur Respir J. 2014 Apr;43(4):983–92. doi: 10.1183/09031936.00046213. Epub 2013 Dec 5. PMID: 24311771.

Aoki F, Kurabayashi M, Hasegawa Y, Kojima I. Attenuation of bleomycin-induced pulmonary fibrosis by follistatin. Am J Respir Crit Care Med. 2005 Sep 15;172(6):713–20. doi: 10.1164/rccm.200412–1620OC. Epub 2005 Jun 23. PMID: 15976370.

“Chronic Obstructive Pulmonary Disease (COPD).” World Health Organization, World Health Organization, www.who.int/news-room/fact-sheets/detail/chronic-obstructive-pulmonary-disease-(copd). Accessed 2 July 2024.

Córdoba-Lanús, E., Cazorla-Rivero, S., García-Bello, M.A. et al. Telomere length dynamics over 10-years and related outcomes in patients with COPD. Respir Res 22, 56 (2021). https://doi.org/10.1186/s12931-021-01616-z

Gao W, Yuan C, Zhang J, Li L, Yu L, Wiegman CH, Barnes PJ, Adcock IM, Huang M, Yao X. Klotho expression is reduced in COPD airway epithelial cells: effects on inflammation and oxidant injury. Clin Sci (Lond). 2015 Dec;129(12):1011–23. doi: 10.1042/CS20150273. Epub 2015 Jul 10. PMID: 26201096; PMCID: PMC4613497.

Maruyama S, Nakamura K, Papanicolaou KN, Sano S, Shimizu I, Asaumi Y, van den Hoff MJ, Ouchi N, Recchia FA, Walsh K. Follistatin-like 1 promotes cardiac fibroblast activation and protects the heart from rupture. EMBO Mol Med. 2016 Aug 1;8(8):949–66. doi: 10.15252/emmm.201506151. PMID: 27234440; PMCID: PMC4967946.

Stanley SE, Merck SJ, Armanios M. Telomerase and the Genetics of Emphysema Susceptibility. Implications for Pathogenesis Paradigms and Patient Care. Ann Am Thorac Soc. 2016 Dec;13 Suppl 5(Suppl 5):S447-S451.

Verhamme FM, Bracke KR, Amatngalim GD, Verleden GM, Van Pottelberge GR, Hiemstra PS, Joos GF, Brusselle GG. Role of activin-A in cigarette smoke-induced inflammation and COPD. Eur Respir J. 2014 Apr;43(4):1028–41. doi: 10.1183/09031936.00082413. Epub 2013 Nov 14. PMID: 24232707.

Yndestad, Arne, et al. “Elevated levels of activin A in clinical and experimental pulmonary hypertension.” Journal of applied physiology 106.4 (2009): 1356–1364.

Zhang, W. et al. Follistatin-like 1 protects against hypoxia-induced pulmonary hypertension in mice. Sci. Rep. 7, 45820; doi: 10.1038/srep45820 (2017).