It is fascinating to look at the long history of medicine and to see how quickly new treatments are adopted and old paradigms discarded. Prior to the 20th century, medicine and spirituality were seen to be intricately linked, with spiritual leaders also playing the role of medical healer, and vice versa. Although modern medicine is no longer associated with spirituality, the dynamics between medicine and spirituality still play out in many parts of the world.

Another fascinating aspect of the history of medicine is how quickly yesterday’s novel treatment can turn into tomorrow’s great hope for an ultimate cure. A mere 50 years ago, most of the public would not be familiar with genetics and gene therapy (Theodore Friedmann first introduced gene therapy for monogenic diseases in 1972).

Today, genetics is widely taught in science lessons all around the world and many people possess an elementary understanding of genetics and its role in medicine. 


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Despite the buzz surrounding gene therapy, as of this writing, there are fewer than 25 cellular and gene therapy products approved by the US Food and Drug Administration (FDA). The two main gene therapy drugs in use today are onasemnogene abeparvovec-xioi (Zolgensma®) for spinal muscular atrophy and voretigene neparvovec-rzyl (Luxturna®) for congenital blindness. However, the number of clinical studies being conducted on gene therapy is vast—in the hundreds.

One of the difficulties of gene therapy is to figure out a suitable way to deliver genetic therapeutics in vivo without the need to transplant cells. The reasons for taking this approach are twofold: it decreases the cost of treatment, and it reduces the potential for adverse effects. 

“The main challenges of in vivo gene delivery include off-target effects of the vector itself or the genetic material and delivery efficiency,” Baliga and Dean wrote in Experimental Biology and Medicine. “Inefficiency of gene transfer, immunological responses, and non-specificity of cell targeting are just a few of the problems associated with viral approaches for gene delivery.”

Reaching the Intended Target

In addition, there are specific impediments when it comes to gene delivery to the lung. Although drugs can be administered easily via the nose or mouth, the drugs must then pass through a number of innate barriers to get to the lungs, such as mucus, pulmonary surfactant, ciliary beating and clearance, and so on. 

In other words, the respiratory tract acts as a natural filtration system designed to keep harmful pathogens out; the problem is that they also make the task of delivering gene therapy to the lungs that much more difficult.

“Even in healthy individuals, the mucus and surfactant present in the lung has small nanosized pores which can impair or even prevent large molecules from passing through the lining fluid layer to the target cells below,” Baliga and Dean wrote. 

One of the challenges in the development of any kind of medical treatment is getting the drug to the target body part without the drug being metabolized away or being reduced to a less potent form. 

However, the good news is that in pulmonary gene delivery, the epithelium is rarely the target. In fact, subepithelial cells are largely untouched when gene delivery agents are used. The key question remains how to bypass nontarget cells (the endothelium, fibroblasts, and smooth muscle) to only reach the cells that the therapy was intended for. 

Viral vectors remain the transportation mechanism of choice for gene delivery. The most common vectors used today are adeno-associated virus (AAV) and lentiviruses. The main advantages of viral vectors are their inherent infectivity and their ability to deliver the therapeutic product in the viral capsid to the target cells. Studies indicate that these properties of viral vectors lead to highly efficient gene delivery as well as expression. 

Many Possibilities in Pulmonary Medicine

Researchers are exploring the potential of gene therapy in the treatment of several pulmonary diseases, including idiopathic pulmonary fibrosis (IPF). Currently, gene therapy is not the mainstay of IPF treatment. Rather, the most common treatment regime prescribed is combination therapy, which is usually prednisone combined with an immunomodulatory agent such as azathioprine. 

Read more about IPF etiology

A form of gene therapy currently under development is SERCA2a. Research has found that patients with IPF had a drastic decrease in SERCA2a levels. Subsequent studies revealed that “the intratracheal nebulization of AAV1.SERCA2a effectively reduced lung fibrosis and vascular remodeling and improved gas exchange,” researchers wrote. Gene therapy trials using the local delivery of AAV1.SERCA2a in IPF mice models improved their lifespan by 45%, compared to bleomycin mice. 

The pulmonary diseases benefitting from gene therapy research also include pulmonary arterial hypertension, cystic fibrosis, and alpha-1 antitrypsin deficiency. If we looked into what genetic researchers are analyzing and discovering each day, we would be amazed by the amount of progress that has been made.  

In Cells, Bisserier and colleagues put it this way: “Novel and improved vectors that can avoid degradation and bypass the immune response after delivery and gene-editing techniques of greater efficiency and precision, along with the development of disease models that are of high fidelity and which are species-specific, will contribute to advances in the field of gene therapy for respiratory diseases.”

References

Bisserier M, Sun XQ, Fazal S, Turnbull IC, Bonnet S, Hadri L. Novel insights into the therapeutic potential of lung-targeted gene transfer in the most common respiratory diseasesCells. 2022;11(6):984. doi:10.3390/cells11060984

Baliga UK, Dean DA. Pulmonary gene delivery-Realities and possibilitiesExp Biol Med (Maywood). 2021;246(3):260-274. doi:10.1177/1535370220965985

Approved cellular and gene therapy products. US Food & Drug Administration. Updated January 3, 2022. Accessed April 27, 2022.