Initially, gene therapy medicinal products were developed to treat monogenic diseases, i.e. diseases caused by alterations in a single gene. Today, gene therapy is also used to treat complex genetic diseases such as cancer.
There is no doubt that ATMPs are highly promising products. However, like any other medicinal product, they must demonstrate a positive benefit-risk balance in terms of quality, safety and efficacy before they can receive marketing authorisation from the relevant regulatory authorities.
BIOTECHNOLOGY PRODUCTS ARE THE PAST AND PRESENT, BUT ABOVE ALL, THEY ARE THE FUTURE
The search for new therapeutic strategies for diseases that currently lack effective treatment options is at the heart of advanced therapies.
Advanced Therapy Medicinal Products (ATMPs) are highly innovative, biotechnology-based medicines which, according to Regulation (EC) No 1394/2007 of the European Parliament and Directive 2001/83/EC, are based on genes (gene therapy), cells (cell therapy) or tissues (tissue engineering) and are intended to prevent or treat complex diseases or conditions with a poor prognosis.
The scientific and technical complexity associated with ATMPs means that their clinical efficacy can sometimes seem almost like an act of magic or faith from the perspective of the traditional pharmaceutical industry. These are products whose mechanisms of action differ significantly from the conventional drug-receptor interactions associated with chemically synthesised medicines or biological medicinal products.
SOMATIC CELL THERAPY MEDICINAL PRODUCTS
Somatic cell therapy medicinal products contain cells that have been manipulated in vitro to alter their biological characteristics or enable them to perform a function different from their original one. These cells may be autologous, allogeneic and/or xenogeneic in origin, and their mechanism of action is based on tissue and organ repair. This makes them one of the cornerstones of regenerative medicine and a promising therapeutic option for degenerative, ischaemic, traumatic and/or inflammatory conditions.
Stem cells are found in all multicellular organisms. They are undifferentiated cells capable of dividing and self-renewing over long periods of time and of differentiating into multiple cell lineages. Originally, the mechanism of action of somatic cell therapy medicinal products was thought to lie in the ability of stem cells to recognise damaged tissues and differentiate into specific cell types. However, most current research suggests that their mechanism of action derives from the ability of stem cells to release trophic factors and bioactive molecules. These activate different signalling cascades and pathways, promoting tissue repair through antifibrotic, angiogenic, anti-apoptotic and antioxidant effects. The mechanism of action of somatic cell therapy medicinal products is therefore considered to rely on the immunomodulatory properties of stem cells. A good example of the immunoregulatory capacity of these products is Alofisel, which is indicated for the treatment of complex perianal fistulas in adult patients with Crohn’s disease.
Perianal fistulas are abnormal tracts that connect the intestinal lumen to the perianal skin, causing local inflammation. The active substance in Alofisel, darvadstrocel, consists of expanded allogeneic stem cells derived from adult human adipose tissue. Darvadstrocel acts through the immunomodulatory effects of stem cells at the site of inflammation, reducing local inflammation and promoting healing of the tissues surrounding the fistula tract.
Somatic cell therapy. Cells may be autologous, allogeneic and/or xenogeneic in origin and are manipulated in vitro to alter their biological characteristics and/or enable them to perform a different function in the recipient tissue.
GENE THERAPY MEDICINAL PRODUCTS
Unlike somatic cell therapy medicinal products, gene therapy medicinal products are intended to treat diseases in which there is a significant genetic cause, whether inherited or acquired. Their active substance contains or consists of a recombinant nucleic acid, and their mechanism of action is based on introducing the recombinant or therapeutic gene into the patient’s target cells. The therapeutic effect may involve the addition, replacement or deletion of genetic sequences and/or the inhibition of the expression of specific gene sequences within the patient’s cells. However, the recombinant gene must first be transferred to the target cells, and vectors are used for this purpose.
Vectors can be either viral or non-viral, although viral vectors are the most widely used. By definition, a viral vector is a virus capable of entering human cells that is used as a vehicle to introduce the recombinant gene into the target cell. Viral vectors used in gene therapy are modified so that they are no longer infectious or pathogenic, retaining only the genetic elements required to deliver the recombinant gene into the target cells.
Viral vectors may also be integrating or non-integrating. Integrating vectors promote the integration of the therapeutic gene into the genome of the target cells, meaning that when these cells divide, the therapeutic gene is passed on to their daughter cells. With non-integrating vectors, the recombinant gene remains as an episome within the target cells rather than integrating into their genome and therefore cannot be passed on to daughter cells.
Whether a viral vector is integrating or non-integrating has significant implications for the product’s mechanism of action and dosing regimen. In general, the use of an integrating viral vector means that the medicinal product only needs to be administered once and that its therapeutic effects may therefore persist throughout the patient’s lifetime. In contrast, when a non-integrating vector is used, the therapeutic effect gradually disappears as the cells containing the therapeutic gene die, meaning that the product may need to be administered again. Adenoviral and adeno-associated viral vectors are non-integrating vectors, whereas gamma-retroviral and lentiviral vectors are integrating viral vectors.
Initially, gene therapy medicinal products were developed to treat monogenic diseases, i.e. diseases caused by alterations in a single gene. One example is Luxturna (voretigene neparvovec), which is indicated for the treatment of adults and children with vision loss caused by inherited retinal dystrophy associated with a mutation in the RPE65 gene. The product’s mechanism of action is based on the use of an adeno-associated viral vector that introduces a functional, non-mutated copy of the gene into the patient’s retina, enabling expression of the corresponding functional human RPE65 protein in the retinal pigment epithelium and helping to restore visual function.
Today, however, gene therapy is also used to treat complex genetic diseases such as cancer, particularly through the use of genetically modified T lymphocytes, better known as CAR-T cells. CAR stands for chimeric antigen receptor, a membrane receptor engineered to bind specifically to tumour cells and activate a cytotoxic response against them, thereby promoting tumour elimination.
One example of this type of medicinal product is Yescarta (axicabtagene ciloleucel), indicated for the treatment of adult patients with diffuse large B-cell lymphoma and/or primary mediastinal large B-cell lymphoma. Yescarta is based on autologous T cells genetically modified ex vivo using an integrating vector so that they express a CAR specifically targeting CD19, a marker expressed by the target tumour cells. The viable anti-CD19 CAR-T cells are expanded and then infused back into the patient, where they can recognise and eliminate CD19-expressing tumour cells, thereby promoting tumour elimination.
Finally, there is no doubt that ATMPs are highly promising products. However, like any other medicinal product, they must demonstrate a positive benefit-risk balance in terms of quality, safety and efficacy before receiving marketing authorisation from the relevant regulatory authorities. Another of the main challenges associated with these products, and one that makes it more difficult for them to reach patients both today and in the future, is the shortage of professionals who combine knowledge of the traditional pharmaceutical industry with expertise in fundamental biomedical sciences.
Gene therapy. Depending on the medicinal product’s mechanism of action, gene therapy may be performed in vivo (e.g. Luxturna) or ex vivo (e.g. Yescarta). In in vivo gene therapy, viral vectors are administered directly to the patient and reach the target cells, where the therapeutic gene is introduced, either through an integrating or non-integrating mechanism, to exert its intended function. In ex vivo gene therapy, the therapeutic gene is introduced into the target cells outside the patient’s body, either through an integrating or non-integrating mechanism. The genetically modified cells are then infused into the patient, where they exert their therapeutic effect.
VALTRIA’S ROLE IN THE NEW ERA OF ADVANCED THERAPIES
At Valtria, we support pharmaceutical and biotechnology companies and research centres in the design and construction of controlled environments for critical processes.
Our expertise in cleanrooms, GMP areas and complex Life Sciences projects enables us to develop facilities tailored to the specific challenges of advanced therapies, ensuring regulatory compliance, operational efficiency and the flexibility required to respond to an evolving market.
Because the future of medicine depends on more than scientific innovation alone. It also requires environments capable of making that innovation possible.
