Libella Gene Therapeutics is developing telomerase gene therapy as a clinical treatment, work that results from more than a decade of studies in mice that show extended life, reduced cancer risk, and improved health. Telomerase acts to lengthen telomeres, the repeated DNA sequences at the ends of chromosomes that shorten with each cell division. Average telomere length in the somatic cells making up any given tissue is a function of the rate of cell division versus the pace at which stem cells produce new daughter somatic cells with long telomeres. Since stem cell activity declines with age, it is no surprise to see telomere length shorten.
Telomerase gene therapy acts in part by extending the working life of somatic cells, and thus the prospect of active cells, burdened with damage due to a longer working life, and the attendant cancer risk has always been a concern. That telomerase gene therapy reduces cancer incidence in mice may be the result of improvements in immune function, particularly cancer immunosurveillance, that outweigh any increase in cancer risk due to increased activity of damaged cells. Mice and humans have very different telomere dynamics, however, so it remains to be seen whether or not the same balance of outcomes is the case in our species. The best way to find out, as ever, is for brave volunteers to try the therapy.
The clinical trial (NCT04133649) has just began recruitment stage. The procedure will consist of a single intravenous injection, followed by six safety and efficacy evaluations. Participants will receive adeno-associated virus (AAV) containing gene expressing telomerase reverse transcriptase enzyme. AAV is expected to move from the circulatory system to tissues, invade cells, and establish telomerase expression inside cells. Viruses will not modify the genome - AAV's genetic material normally exists separately in the cell cytoplasm (as an episome).
Formally, the study is phase I trial, which limits the main goal - whether it is successful or failed attempt - to safety only. In this case, the primary goal was declared as the incidence of adverse effects. Determination of dosing and tolerability is an important first step in all gene therapies. High doses of viral particles result in significant immunological reaction. Moreover, liver damage is a common adverse effect in early gene therapies, because of liver's participation in blood filtering. In addition, telomerase introduces additional risk on its own. In 85% cases of cancers, telomerase is found upregulated, which raises concerns about potential oncogenicity of AAVs with hTERT gene.
The trial is accompanied by two similar phase I attempts (NCT04133454, NCT04110964), which target Alzheimer's disease and critical limb ischemia. Patients participating in the trial will be enrolled in their country of origin and will travel to Colombia. Patients will stay in Colombia for a few days while the treatment is administered and hospitalized for observation. Patients will then return to their country of origin and will be followed-up per the study protocol.