Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5665_Библиотеки_им_академика_М_И_Перельмана

Scientists have long ago linked genes to biological traits and features. Hershey and Chase demonstrated in 1952 that DNA was the basis for inheritance and the early experiments that followed provided the basic understanding of how DNA is passed from parent to progeny and used as a set of instructions for a cell[1]. Visionary scientists hypothesized that genetic modification through the introduc­tion of exogenous DNA could be the basis for disease treatments[2]. By providing new genetic coding sequences, one could reprogram cells to perform a new func­tion or restore a missing function. Instead of providing a protein, a chemical drug, or a metabolite, these scientists were dreaming of ways to alter genes. It was in July of 2012 that the European Medicines Agency (EMA) granted approval for the first gene therapy product, Glybera®, an adeno‐associated viral vector engineered to deliver a corrected form of the enzyme lipoprotein lipase to the muscle tissue of patients suffering from a severe deficiency in this enzyme. Five years later, three approvals by the U.S. Food and Drug Administration (FDA) marked a breakout in which two exvivo gene‐modified products (Kymriah®, Yescarta®) and one direct in vivo gene transfer product (Luxturna®) were approved. Collectively termed gene therapy (GT), these products established a new pharmaceutical classifica­tion and the formal recognition of genetic modification of human cells as a new treatment paradigm.

as a biological medicinal product that consists of a recombinant nucleic acid that once administered to human beings can regulate, repair, replace, add, or delete a genetic sequence; thus, GTMP mediate their therapeutic, prophylactic, or diag­nostic effect through the recombinant nucleic acid sequence they contain, or through the product of genetic expression of this sequence[12]. Although there is no universal definition of GTP, the World Health Organization (WHO) has recently published a document aimed to achieve worldwide regulatory consensus on this definition [13]. For now, both developers and regulatorsdistinguish GTP from therapeutic proteins (so‐called “biotech” products) by categorizing them as “advanced” therapy products, and regulatory agencies anticipate the same level of quality, safety, and efficacy evidence to attain a positive benefit:risk assessment to support the approval and commercialization of a new GTP/GTMP[6].

solid scientific evidence (e.g. epidemiological, therapeutic, and/or pathophysio­logical) demostrating that the chosen biomarker can also consistently and accu­rately predict a clinical outcome, either a benefit or a harm. In this case, the biomarker can be proposed as a surrogate support product development, but acceptance will be granted on a case‐by‐case basis, and very rarely to replace a clinical endpoint.

The use of biomarkers in the development of gene therapy products is further

biodistribution study be done in combination with an animal toxicology study because the location and persistence of the GT vector can help with the interpre­tation of toxicology assessments. In addition, the extent of long‐term follow‐up (LTFU) in patients may be guided by product biodistribution studies in animals. It also recommends developers to sample a panel of tissues, at a minimum (blood, injection site(s), gonads, brain, liver, kidneys, lung, heart, and spleen) and assess vector copy number with a sensitivity of not less than 50 copies per microgram of cellular DNA (or about 10e5 cells). General recommendation is that five (5) animals/sex/timepoint and for collections to include tissues prior to peak, steady‐ state (i.e. plateau), and declining (if feasible)[8, 25]. Similar considerations for the concurrent evaluation of biodistribution and toxicity in pre‐clinical studies are contemplated by EMA with a clear recommendation to adequately justify the choice of endpoints and biomarkers predictive of toxicity in animals[26].

for the second NIH‐approved human gene transfer study. Shortly after the 1988 TIL approval, a second protocol was approved by the NIH that involved the gene correction of peripheral blood cells for the treatment of severe combined immune deficiency (SCID) caused by the adenosine deaminase (ADA) deficiency. As before with the gene marked TIL, this approach used retroviral‐mediated gene transfer and careful consideration was given to the risks associated with a geneti­cally modified virus and the generation of RCR. As with the TIL study, biomarkers for RCR indicated no RCR was generated in study subjects and the biodistribution and persistence of genetically modified cells was assessed for up to 10 humans. Interestingly, a biomarker of functional activity of the gene‐modified cells was assessed by measuring ADA activity present in peripheral blood sam­ples[27]. This second study reported results for all three biomarkers and it has set the standard for many years to come. It was not until the mid‐2010s that this set of biomarkers was substantially reevaluated and expanded with the introduction of high‐dose systemic AAV gene therapy and the expansion of LVV gene‐modified cell products.