Global trends in advanced therapies

Both gene therapy and cell therapy fall under the umbrella of advanced therapies, but they work differently, so it's important not to confuse them.

Cell therapyit involves the use of living cells to treat diseases. Cell therapy consideration, as opposed to traditional cell transplantation—such as bone marrow transplantation— is provided by substantial modification of the cells, for example, by expanding or modifying them, and / or use with a different function or place than they originally had in the organism (3).

Figure 1. Cell therapy. Source: Advanced Therapies Report: Cell therapy and gene therapy. Roche Institute (4).

Gene therapyit consists of modifying or replacing defective or absent genes in an individual's genome, or doing so in a cell to improve its action or therapeutic capacity. This may involve the use of viral vectors to introduce desired genes into the body or direct gene editing with techniques such as CRISPR-Cas9, therapeutic DNA/RNA-based technologies or chimeric therapies, as is the case with CAR-Ts ( 3).

Some therapies use a combination of the two. These work by altering genes in specific cells and introducing them once modified into the patient's body (4).

The different types of gene therapy can be classified according to the objective and the methodology used (5):

• Type of target cell, germ or somatic. When GT is applied to germ cells (sperm or eggs), they cause changes that will affect the individual's future descendants. On the contrary, when GT is used in somatic cells, it only affects the treated individual, without affecting the cells involved in reproduction, and therefore the modifications are not inherited.
• Strategy: ex vivo and in vivo. In the strategy ex vivo, the target cells are removed and reintroduced into the same patient after being modified in the laboratory. In the strategy in vivo, the administration of the correcting or modifying genetic material is carried out directly to the patient.
  • To insert genetic material into the cells, both in the strategies ex vivo as in in vivo, elements known as “vectors” can be used that act as safe and effective carriers of gene therapy. This vector can be viral (when it comes from a virus) or non-viral (like liposomes).
  • Gene therapies can also be done without using vectors, in which the genetic material can be introduced into the cell by direct injection or by using physical methods such as electroporation, which facilitates the entry of nucleic acids into the cell.
• Approaches: additive and substitutive. In additive GT, the most widely used and advanced, the genetic material is incorporated with its own regulatory elements, while in substitutive GT, the genetic material remains in its natural context, and is subjected to the expression controls of the cell in which it is introduced.

Figure 2. Different ways to administer gene therapy. Source: Report Advanced therapies: Cell therapy and gene therapy. Roche Institute (4).

The following table specifies the factors that can represent a threat or opportunity for gene therapies, in the different areas of PESTLE (political, economic, social, technological, legal and environmental).

Taulí 1. Key factors in the different areas of PESTLE

The global gene therapy market, in terms of revenue, generated $7,54 trillion by 2022 and is expected to reach the 17,2 trillion by 2027, which represents a compound annual growth rate (CAGR) of 22% from 2023 to 2030 (6).

Figure 3. Global gene therapy market. Source: www.businesswire.com

Certain factors may help the expected growth of the global market (7):

• Gene therapy approvals are on the rise.
• Investment in gene therapy research and development is on the rise.
• Expansion of the area of ​​advanced therapies and technologies for the administration of genetic material.
• Biotech companies' investments in acquisitions, mergers or collaborations as a key strategy to increase internal expertise.
• The increase in the prevalence of cancer
• The increase in the visibility of minority diseases of genetic cause.
• The increase in the size of the population.

However, the high cost of gene therapy is restraining the growth rate of this market.

The gene therapy market can be segmented based on vector type, therapy type, applications, and region (8).

• Vector type: divided between viral or non-viral vector. The segment of viral vectors, in turn, can be divided according to the type of virus used: retroviruses, lentiviruses, adenoviruses, herpesviruses, poxviruses and others. The non-viral vector segment can be classified into several categories based on their properties and delivery methods; plasmid vectors, gene gun, electroporation, lipofection, nanoparticles, ultrasound and others. The non-viral vectors segment has the largest size within the gene therapy market, and is estimated to have the peak growth during 2027. In the viral vectors segment, retroviruses have experienced a revenue growth of more than 20 % during 2022.

Figure 4. Gene therapy market size and trend segmented by vector type. Source: www.grandviewresearch.com

• Type of therapy: The market is classified between therapies ex vivo i in vivo. The therapies segment in vivo, had a higher market share in 2020. Moreover, it is a minimally invasive and effective method, which promotes the growth of the segment and thus promotes the growth of the market.

Figure 5. Size and trend of the gene therapy market segmented by type of therapy (ex vivo / in vivo). Source: www.globenewswire.com

• Applications: The gene therapy sector has developed mainly in oncology, minority diseases, cardiovascular, neurological and infectious diseases. The oncological disorders segment holds the largest share of the gene therapy market. On the other hand, spinal muscular atrophy dominated the segment by 2022 as a revenue share of 43,4%. Although it is a rare disease, it is one of the most common fatal hereditary diseases in childhood. Hereditary retinal diseases are expected to experience a compound annual growth rate till 2027. The increase in R&D activities focused on the treatment of eye diseases, has boosted this segment.

Figure 6. Gene therapy market size and trend by application. Source: www.grandviewresearch.com

• Region: The gene therapy market is located in North America, Europe and Asia-Pacific. North America dominated the market during 2022 and accounted for more than 65% of global revenue. This region is expected to become the most important manufacturer of gene therapies, considering the number of approvals and revenues they will generate in the coming years. Asia-Pacific is estimated to be the regional segment with the highest increase in growth between 2023 and 2030. This is attributed to the large population with unmet medical needs and the growing demand for new technologies for the treatment of rare diseases It may also be due to the local presence of the main companies in the sector and the increase in investment by governments.

Figure 7. Gene therapy market size and trend by application. Source: www.grandviewresearch.com

Advanced therapies are currently a field in medicine with a high growth potential, thanks to the positive results that provide the opportunity to have more effective treatments for complex diseases. Thus, advanced therapies represent a sector of high strategic interest, and its market can imply a strong economic boost.

However, these therapies present some challenges, discussed in more detail in the next section, such as the high cost of production, which drives small biotech and public sector companies to seek strategic collaborations with manufacturers and large pharmaceutical companies. This also helps to boost the market expansion of these therapies. In addition, investments in this field are growing a lot, which boosts the market even more.

At present, the main players are focusing on the study of new gene therapy products to take advantage of the market growth opportunity. Most of the products are in the preclinical phase, although some are already in the clinical phase awaiting approval in the coming years. This point is important, as regulation in these trials is stricter than regulation in trials with other therapies, to ensure maximum safety. Trials in advanced therapies are also different in that they require specialized spaces, such as biological safety cabinets, for the preparation of medicines.

Figure 8. Number of clinical trials in advanced therapies existing worldwide. Source: Map of capabilities in advanced therapies of biotechnological companies of AseBio.

In the last twelve years, the European Medicines Agency has given green-light to eight advanced therapy drugs. In Spain, currently, there is a high number of clinical trials with this type of therapy, a fact that reflects the growth trend and opportunity of this market, and confirms the need to continue with public-private collaboration for keep moving forward

There are numerous companies involved in the gene therapy market, as listed below. Some of them have drugs that are already approved and can be used for the treatment of genetic disorders, and others have drugs in the preclinical and clinical stages that are waiting to be approved by regulatory authorities.

Taulí 2. Competitive landscape of public gene therapy companies, according to technique and development phase (9).

Figure 9. Competitive landscape of public companies that develop gene therapies. Source: https://twitter.com/paras_biotech/status/1498865208751804428/photo/1

Taulí 3. Most relevant institutions in gene therapy in the United States and Europe (10).

Taulí 4. Main journals on gene therapy.

Gene therapy legislation aims to protect humans, the general public and the environment. Carrying out gene therapy clinical trials with genetically modified organisms, as vectors, raises unique safety issues. This area is governed by a series of laws and guidelines, some unique to this field, as well as others relevant to any clinical setting.

The main regulatory institutions in Europe and the United States are the following (10):

In Spain, the authorities involved in the authorization of clinical trials and aspects related to genetically modified organisms (OMG) are theSpanish Medicines and Health Products Agency and the Interministerial Council ofOMG. The aspects related to the OMG of clinical trials with medicines for human use, which contain or consist of OMG, are regulated by the intentional release framework. Requests for authorization in the context of clinical trials and in the context of OMG are not linked (that is, the applicant can decide when to submit the applicationOMG) (11).

Spain is one of the reference countries in advanced therapies, both for the high level of science and publications, and for the number of clinical trials, in all types of advanced therapies (more than 100 per year).

The following tables show some of the companies, hospitals and research centers that are part of the ecosystem.

Taulí 5. Interesting Spanish companies that do research and innovation in gene therapy.

Company	Description	Enllaç
	Develops and manufactures lentiviral vectors. European leader working under EMA and FDA regulations.	here
	Factory of vectors for clinical trials on gene therapy treatments.	here
	It develops a gene therapy based on the expression of the telomerase gene, intended to treat diseases related to aging.	here
	Exploit protein splicing to develop the next generation of gene therapies.	here

Taulí 6. Spanish hospitals that carry out research and innovation in gene therapy.

Taulí 7. Interesting Spanish research centers that carry out research and innovation in gene therapy.

In recent years, interest in advanced therapies has grown significantly in Catalonia. There is a significant number of organizations, from research and development centers, entrepreneurial fabric, industry, investors and public administration, which form a very dynamic and constantly growing ecosystem.

There are also new strategic initiatives, such as Center for Advanced and Emerging Therapies of Catalonia (Hub), an infrastructure that will be responsible for guaranteeing the connection between the generation of advanced therapies, within the framework of the public health and research and innovation systems, and the industrial fabric. This project is promoted by the Government of the Generalitat of Catalonia and coordinated by Biocat (12).

The main goals of the future Hub of Advanced Therapies are based on bringing these therapies to the patients who need them as soon as possible. For this reason, they plan to work in the field of research, in infrastructure and manufacturing and with the business fabric. In the Action Plan presented by Biocat, you can find detailed information about the future Hub.

The Parc Taulí University Hospital is committed to advanced therapies, this being one of its strategic lines to which it dedicates resources and facilitates its growth. In this sense, it actively participates in clinical trials, it has promoted the Advanced Therapies Platform - of which the Center for Genomic Medicine, the Clinical Trials and Pharmacy Support Unit are part - in order to participate and collaborate in the implementation of these therapies, and is in contact with the CBATEG (Centre for Animal Biotechnology and Gene Therapy) of the Autonomous University of Barcelona, ​​to be able to carry out gene therapy studies together. The Parc Taulí Research and Innovation Institute (I3PT) also supports research and innovation in advanced therapies.

Currently, the Parc Taulí University Hospital participates in 4 clinical trials on advanced therapies:

1. Randomized, placebo-controlled, double-blind, multicenter phase IIb study to evaluate the efficacy and safety of HepaStem in patients with acute and chronic liver failure (ACLF) – DHELIVER. Promoter: Promethera Biosciences. IP: Jordi Sánchez Delgado
2. Open-label, multicenter study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of RO7248824 in participants with Angelman Syndrome. Promoter: Roche Farma. IP: Ana Roche Martínez
3. Phase I/II, open-label, multiple-dose, step-escalation clinical trial to evaluate the safety and tolerability of GTX-102 in pediatric patients with Angelman Syndrome (AS). Promoter: Ultragenyx Pharmaceutical Inc. IP: Ana Roche Martínez
4. Implantation of skeletal muscle-derived cells for the treatment of faecal incontinence: a phase III, randomized, controlled, double-blind, two-treatment-arm clinical study. Promoter: Innovacell AG. IP: Laura Mora López.

In the coming years, research and innovation focused on this area is expected to increase significantly, to be in line with the future of personalized medicine.