Maintaining a long and healthy life with a new intranasal and injectable gene therapy | Health

With the global growth of the elderly population, it is essential to have an effective and diversified means of mitigating the impact of aging on human health, whether socio-economically or medically. A recent study demonstrated the efficacy of using cytomegalovirus in mice as a gene therapy vector for two age-protective factors to prolong life up to 41.4% of its age. It extended the median lifespan of treated mice without increasing cancer risk while improving biomarkers related to aging, including glucose tolerance, exercise performance, loss of body mass, hair loss, shortening of telomeres and deterioration of mitochondrial structure. (Also read: 10 daily habits that accelerate aging)

The two age-protective factors, namely, are “Telomerase Reverse Transcriptase Enzyme” and “Follistatin Protein”.

The goal of achieving a healthy lifespan remains a difficult topic in biomedical science. It is well established that aging is associated with a decrease in the number of telomere repeats at the ends of chromosomes, in part due to insufficient telomerase activity. Importantly, the biological functions of the telomerase complex rely on telomerase reverse transcriptase (TERT).

TERT plays a major role in activating telomerase, which in turn lengthens telomere DNA. Since telomerase promotes cell proliferation and division by reducing erosion of chromosome ends in mitotic cells, TERT-deficient animals have shorter telomeres and shorter life spans. Recent studies in animal models have supported the therapeutic efficacy of TERT in increasing healthy longevity and reversing the aging process.

Telomere shortening also increases the risk of heart disease. The follistatin (FST) gene encodes a monomeric secretory protein that is expressed in almost all mammalian tissues. In muscle cells, FST functions as a negative regulator of myostatin, a signal protein that inhibits myogenesis. Overexpression of FST is known to increase skeletal muscle mass in transgenic mice by 194-327% by neutralizing the effects of various TGF-b ligands involved in muscle fiber breakdown, including myostatin and inhibition complex activin. FST knockout mice have smaller and fewer muscle fibers, exhibit growth retardation, skeletal abnormalities and reduced body mass, and they die a few hours after birth. The acceleration of these degenerative tendencies after FST knockout underscores the important role of FST in skeletal muscle development.

Aged mice showed loss of motor unit function with impaired neuromuscular junction transmission. Follistatin expression in aged mice has been shown to not only increase muscle mass but also improve neuromuscular function. These results strongly imply the therapeutic potential of FST in the treatment of muscular dystrophy, muscle loss, and impaired neuromuscular function caused by aging or microgravity. Based on this evidence and supporting hypotheses, TERT and FST are among the leading candidates for gene therapy protocols aimed at improving healthy lifespan.

As more longevity-promoting factors are discovered, it is natural to explore potential high-capacity vectors to deliver multiple genes simultaneously. Unlike adeno-associated virus (AAV), lentiviruses, or other viral vectors currently commonly used for gene delivery, cytomegaloviruses (CMVs) have a large genome size and a unique ability to incorporate multiple genes. Additionally, cytomegaloviruses do not integrate their DNA into the host genome during the infection cycle, thereby mitigating the risk of insertional mutagenesis.

CMV infections are usually asymptomatic in most healthy adults, but can become problematic in newborns or transplant patients. Human CMV (HCMV) has been shown to be a safe delivery vector for the expression of therapeutic proteins in human clinical trials (20). Mouse CMV (MCMV) and HCMV are similar in many respects including viral pathogenesis, homology, viral protein function, viral gene expression, and viral replication.

The cytomegalovirus vector has proven to be a potent foreign gene delivery vector and is used in different immunotherapies including cancer, tuberculosis (TB), acquired immunodeficiency syndrome (AIDS), malaria and many more. others. Using MCMV as a viral vector, researchers examined the therapeutic potential of TERT and FST gene therapy to compensate for biological aging in a mouse model and demonstrated a significant increase in lifespan, as well as positive effects on metabolic and physical performance. The researchers believe that further studies could elucidate the capacity and effectiveness of the full CMV cargo. Translational studies are needed to determine if the results can be reproduced in human subjects. (ANI)


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