Cell and gene therapies approved by the FDA. Below is a list of all known cell and gene therapy products that have been authorized by the Office of Advanced Tissue and Therapies (OTAT), a division of the U.S. UU. Currently, 41 cell and gene therapies have been approved in the United States.
U.S. and European regulators could approve up to 17 gene therapies this year, and a senior U.S. Food and Drug Administration (FDA) official predicts that 2024 will be a “great year” to address key challenges for developing cell and gene therapies, especially for rare disorders. Gene therapy drugs have revolutionized the medical field by providing a specific approach to treating genetic disorders. In this section, and in Table 1, we will provide an overview of the various gene therapy drugs that have been developed, their advantages and disadvantages, as well as the challenges faced in their practical use.
The size of the siRNA ranges from 20 to 25 base pairs. One of the main advantages of siRNA is its high specificity due to its 100% complementarity with the target mRNA. This makes it an attractive drug candidate for diseases caused by specific genetic mutations. In addition, siRNA has been shown to be effective in delivering drugs to the brain, a feat notoriously difficult to achieve.
These RNAs are larger than other small RNAs and are usually 26 to 32 nucleotides in length. ShRNAs range in size between 19 and 29 base pairs and have the advantage of being relatively resistant to degradation and renewal, providing long-lasting gene silencing effects. ASOs are a type of drug that has received significant attention in recent years because of their potential in gene therapy. ASOs are single strings of DNA or RNA that are complementary to a specific mRNA sequence.
They act by binding to the target RNA and blocking the translation of certain proteins, thus modulating gene expression. ASOs are relatively small in size, ranging from 18 to 30 base pairs, allowing them to easily penetrate cell membranes and attack long non-coding RNAs (lncRNAs) located both in the nucleus and in the cytoplasm. Despite their potential therapeutic benefits, ASOs have several limitations that need to be addressed. A major concern is undesired effects, in which ASOs bind to unwanted RNA sequences and cause unwanted biological effects.
In addition, ASOs may have insufficient biological activity, limiting their efficacy in gene therapy. mRNA is a promising drug for gene therapy. It is a single-stranded RNA molecule that corresponds to the genetic sequence of a gene and is read by a ribosome in the process of protein synthesis. By introducing the corrected mRNA into cells, they can receive the right model to create healthy proteins, which can help treat a variety of genetic disorders. TALENs are a promising gene therapy tool that can be used to cut specific DNA sequences.
TALENs are restriction enzymes that have been designed to bind and cut DNA in a very specific way. Their size ranges from 32 to 40 base pairs and they are able to tolerate some mismatches, resulting in an edition that does not deviate from the objective. In addition, TALENs have moderate design requirements. PMO oligomers range in size from 6 to 22 base pairs and have been shown to be resistant to a variety of enzymes present in biological fluids, making them ideal for in vivo applications.
Bare DNA, which is simply DNA without any associated protein, has been extensively investigated as a gene transfer tool for various tissues, such as skin, thymus, heart muscle, skeletal muscle and liver cells. This method involves direct injection of DNA into the target tissue, allowing for the transfer of a gene with a size range of 2 to 19 kb. In this section, and later in Figure 2, we will focus on the second facet of gene therapy, namely, carriers, which serve as conduits for delivering gene therapy drugs to designated destinations. Our goal is to provide a comprehensive compendium of the carriers currently used in gene therapy practices, accompanied by an exhaustive analysis of their respective limitations, benefits, drawbacks and authorized utility in gene therapy products, as well as illustrative examples highlighting their applications.
As nature's original “genetic therapists”, viruses possess the tools necessary for cellular entry and the efficient dissemination of their cargo genetics. Scientists have taken advantage of this natural ability and have reused viruses for human gene therapy by replacing their original genetic material with therapeutic gene therapy drugs. This process has led to the development of numerous viral vectors that are now used in gene therapy. In the following sections, we'll explore some of the most commonly used viral vectors for gene therapy.
Ex vivo gene therapy is a process by which cells outside the body are genetically modified and then returned to the patient. Retroviral vectors are one of the commonly used viral vectors for ex vivo gene therapy and have been used in several clinical trials. Retroviruses are small RNA viruses that replicate through a DNA intermediate. These vectors are suitable for ex vivo gene therapy, such as transduction of CD34+ hematopoietic stem cells from bone marrow or peripheral blood lymphocytes. The retroviral vector has a size limit of 10 kb, meaning that it can supply genetic material from a limited size.
LVVs are a type of viral vector that is spherical and is composed of single-stranded RNA. These vectors are commonly used in ex vivo gene therapy applications for T cells. LVVs have an upper limit of 8 kb, making them suitable for larger genes. One of the main advantages of LVVs is their ability to transfer genes persistently into dividing cells.
However, they can also pose a safety risk, as they can cause unnecessary non-target insertional mutations. Adeno-associated virus (AAV) is a small, double-stranded, non-enveloped DNA virus that has gained popularity as a vector for gene therapy. AAV is a good option for in vivo gene therapy, as it has good biological characteristics and is neither immunogenic nor pathogenic. AAV has high gene transduction efficiency and ease of use on a large scale, which has led to its use in a variety of somatic gene therapy applications.
One of the limitations of AAV is its packaging capacity, which is limited to 4.5 kb. However, AAV is known for its genetic stability, making it an attractive vector for gene therapy. The AAV production process is complicated and expensive, which can be an obstacle to its wider use. Herpes simplex virus type 1 (HSV) is a viral vector that has shown great promise for somatic gene therapy in vivo.
With a packaging capacity of up to 40 kb (defective replication) and 150 kb (amplicon), HSV-1 can house large transgene cassettes, making it an attractive option for gene therapy. In addition, the strong tropism of HSV-1 in neurons makes it an ideal candidate for the treatment of diseases of the central nervous system. Alphaviruses are single-stranded RNA viruses that have been used in gene therapy as viral vectors for the in vivo delivery of somatic cells. These enveloped alphavirus particles are made up of a protein capsid structure surrounded by proteins.
spike-shaped membrane. They recognize surface proteins, such as laminin and heparin receptors, in mammalian and insect cells, and carry the RNA genome to the cell cytoplasm for immediate RNA replication. Bacteriophages, also known as phages, are a type of viral vector that has become increasingly popular in gene therapy. These viruses infect and replicate only in bacterial cells and are the most abundant biological agent on Earth.
They consist of a nucleic acid genome enclosed in a layer of capsid proteins encoded by phages. Epstein-Barr virus (EBV), also known as human gammaherpesvirus 4, is a double-stranded DNA virus with a limit of 172 Kbp. The development of non-viral vectors for gene therapy has been one of the main objectives in recent years to address the limitations of viral vectors, such as their high production cost, complex manufacturing processes, the possibility of inducing inflammatory responses, etc. Non-viral vectors offer a more affordable, simple and effective alternative.
Numerous non-viral vectors have been created, each with unique advantages and disadvantages. In the next section, we'll explore some of the most notable non-viral vectors used in gene therapy. Gold nanoparticles (AuNP) have become a promising non-viral vector in gene therapy, with advantages such as easy surface modification and their unique optical properties. These inorganic biomaterials can be synthesized and modified with chemical and biological molecules, making them a versatile tool for drug delivery and molecular diagnostics.
The surface of AuNPs allows the efficient attachment of several biomacromolecules through chemisorption, chemical conjugation and electrostatic interactions. In addition, their small size of 1 to 100 nm and their absence of toxicity make them an attractive option for use in gene therapy. The TMC-g-PEG polyplex modified with the REDV peptide is designed to attack vascular endothelial cells (VEC) and deliver miRNA-126 to these cells. The vector is composed of a short peptide, Arg-Glu-Asp-Val (REDV), linked to trimethylchitosan (TMC) through a bifunctional poly (ethylene glycol) (PEG) linker.
Magnetic nanoparticles, a type of non-viral vector, have aroused considerable interest in recent years because of their potential in the transmission of genes. These nanoparticles consist of a magnetic material, usually iron, nickel or cobalt, and a functional chemical component. Magnetic nanoparticles are inherently biocompatible and their magnetic moments can be controlled by externally applied magnetic fields to take advantage of their nanoscale behavior. In addition, magnetic nanoparticles are relatively easy to synthesize and modify, making them an attractive option for gene therapy applications.
A possible application of magnetic nanoparticles in gene therapy is their use in targeted delivery to specific cells or tissues. By functionalizing the surface of magnetic nanoparticles with target fractions, such as antibodies or peptides, these particles can be targeted to specific cell types or even to individual cells within a tissue. This can increase the specificity and efficacy of gene therapy while minimizing unwanted effects. Lipoplexes are a class of non-viral vectors used in gene therapy that have attracted attention because of their ability to effectively transport genetic material to target cells.
These vectors are made up of cationic lipids of an amphiphilic nature, meaning that they have both hydrophilic regions as hydrophobic. Normally, a charged cationic head group is attached by a linker, such as glycerol, to a double hydrocarbon chain or to a cholesterol derivative. Lipoplexes can be used both in vitro and in vivo for gene delivery applications. One of the main advantages of lipoplexes is that they are relatively easy to produce compared to viral vectors.
In addition, they do not induce an inflammatory or immune response from the host, which can be a significant advantage for gene therapy applications. Graphene is a non-viral vector that has been extensively studied for its potential use in gene therapy. As a single layer of carbon atoms arranged in a hexagonal lattice, graphene is incredibly thin, light and strong. However, its use as a gene therapy vector is not without challenges. The GO-PEI-10K complex has attracted attention for its low cytotoxicity and high transfection efficiency.
This complex is formed by joining GO with a cationic polymer, polyethylenimine (PEI), with two different molecular weights of 1.2 kDa and 10 kDa. The resulting complex is stable in physiological solutions and has been shown to have significantly reduced toxicity to treated cells compared to pure PEI-10k polymer. Quantum dots (QDs) have been proposed as an innovative type of non-viral vector in gene therapy. Thanks to quantum mechanics, these semiconductor nanocrystals have unique electronic and optical properties that are different from those of bulk material.
QDs have a narrow emission peak, an emission wavelength that depends on size, and a wide excitation range that could be used for several biomedical applications, such as molecular imaging, biosensing and diagnostic systems. Mesoporous silica nanoparticles (MSN) are an attractive vector for gene therapy due to their adjustable size, biocompatibility, and large surface area. The porous structure of MSNs provides a large surface area, allowing functional groups to adhere to the surface of the particle. MSNs offer easily adjustable particle and pore sizes, larger surface areas, and a simple mesoporous or hollow structure, making them ideal for drug delivery applications.
Ferritin, a spherical nanobox formed by the self-assembly of heavy and light polypeptide chains, is a promising non-viral vector for gene therapy due to its natural metal transport function and its versatility in loading. Ferritin has a small and uniform size, limited to 8 nm in diameter, allowing for efficient cell uptake and intracellular trafficking. It is also very stable under a variety of conditions, including high pH and temperatures. In the world of gene therapy, in addition to therapeutic genes and their carriers, there are also physical delivery methods that can improve the efficiency and effectiveness of gene delivery. We can think of these physical vectors as accelerators that improve the performance of gene therapy vehicles.
Some of these physical vectors can even act as gene delivery vehicles themselves. Let's explore the various physical vectors used in gene therapy to learn more about their unique characteristics and advantages. Microneedling (MN) is a promising tool in gene therapy that can penetrate the stratum corneum, which is the main barrier to drug delivery through the skin. There are different types of MNs, such as metallic MnS, coated MnS and MnS in solution.
MnS has been shown to be effective in delivering low molecular weight and high molecular weight agents, including nucleic acids, with ease of administration and without significant pain. This painless and patient-friendly feature of maternal medications allows for self-administration. In addition, the low production cost of maternalized drugs makes them an option attractive for marketing. MNs have been used for the transdermal delivery of siRNA, low molecular weight drugs, oligonucleotides, DNA, peptides, proteins and inactivated viruses.
Electroporation has become a widely used method for efficient gene delivery in gene therapy. It involves the use of short high-voltage pulses to temporarily break down the cell membrane, allowing the transfer of genetic material to cells. Gene therapy and tissue engineering can be combined to create a novel solution for repairing damaged tissues, known as a gene-activated matrix (RANGE). A GAM offers the possibility of restoring the structure and function of damaged or dysfunctional tissues.
A GAM is a scaffold made of biomaterials that can be seeded with therapeutic genes to direct and maintain gene expression. It can be used for both in vivo and ex vivo approaches, as it provides a three-dimensional template for tissue regeneration. High-pressure hydrodynamic injection is a method of gene delivery that involves the rapid injection of a large volume of pDNA. This technique is simple, convenient and highly efficient, making it a versatile tool for a variety of applications in gene therapy.
Hydrodynamic injection uses a high-pressure flow of fluid to carry DNA directly to the liver or other specific tissues. The process is thought to work by briefly disrupting the plasma membrane, allowing DNA to enter cells. One of the main advantages of high pressure hydrodynamic injections is its simplicity. This method does not require specialized equipment or extensive training and can be easily performed by researchers with minimal experience in gene administration.
In addition, hydrodynamic injections are highly effective, with transfer rates of up to 60% in some studies. This makes it a useful tool for a variety of applications, including gene therapy, vaccine development, and genetic function studies. In this section, and in Table 3, we will focus on the culmination of gene therapy initiatives—that is, on the variety of approved human gene therapy products that have successfully overcome the rigors of the market. These products have moved gene therapy from an area of promising potential to the field of practical application.
We will strive to present a comprehensive inventory of these products, accompanied by an in-depth analysis of their underlying mechanisms, as well as a clarification of their respective advantages and limitations. IMLYGIC (Talimogenelaherparepvec) is an FDA-approved gene therapy product used to treat melanoma and pancreatic cancer in adults. Retinal dystrophy, caused by the biallelic mutation RPE65, leads to progressive loss of vision and, eventually, to blindness. However, LUXTURNA, a gene therapy product, has been approved by the U.S.
FDA. Department of State and the EU FDA for the treatment of this condition. Spinal muscular atrophy (SMA) is a rare genetic disorder caused by mutations in the SMN1 gene, which leads to progressive motor neuron degeneration and, ultimately, to muscle weakness and atrophy. Among the types of spinal muscular atrophy, type I is the most serious and often fatal.
However, the approval of zolgensma (onasemnogene Abeparvovec) by the U.S. Department of State offers new hope to pediatric patients children under 2 years of age with SMA type I. Defibrotide, also known as Defitelio or defibrotide sodium, is a gene therapy product that has been approved by the U.S. Department of Justice and the EU FDA for the treatment of a rare and potentially fatal condition known as sinus obstruction syndrome (SOS) or venoocclusive disease (VOD) with multiple organ dysfunction.
Defibrotide is a combination of single-stranded OligoDNAs with aptameric functions that are obtained from porcine mucosal tissue through controlled depolymerization. ADSTILADRIN is a gene therapy based on non-replicating adenoviral vectors that uses a recombinant adenovirus serotype 5 vector. The vector is designed to deliver a copy of a gene that encodes human interferon alpha 2b (IFNα2b) to the urothelium of the bladder. After intravesical instillation, ADSTILADRIN causes cell transduction and transient local expression of the IFNα2b protein, which is expected to have antitumor effects.
Multiple myeloma is a type of blood cancer that affects plasma cells. It occurs when these cells become abnormal and grow out of control, leading to the production of excessive amounts of abnormal proteins. The U.S. FDA The US and the EU FDA have approved ABECMA (idecabtagen vicleucel)), a gene therapy for multiple myeloma.
CARVYKTI (ciltacabtagene autoleucel) is a gene therapy product approved by both the U.S. Department of State and EU FDA for the treatment of adults with multiple myeloma. The product uses a lentiviral vector (LVV) to introduce a chimeric antigen receptor (CAR) against the B-cell maturation antigen (BCMA) into the patient's own T cells. After being genetically modified ex vivo, T cells can attack and kill cancer cells that express BCMA.
Ex vivo modulated autologous T cells are transduced with the gamma-retroviral vector, which expresses a chimeric antigen receptor (CAR) composed of a murine anti-CD19 single-chain variable fragment and CD28 co-stimulatory domains and the CD3-zeta. After autologous T cells are collected from patients using leukapheresis, the cells are enriched in a closed system at the YESCARTA manufacturing center. Transfected T cells are activated with anti-CD3 and IL-2 antibodies, transduced with a retroviral vector that expresses the CAR gene, which acts against CD19, and re-infused into the patient after less than 10 days of manufacturing. Infusion of T cells with CAR attacks and kills cancer cells that express CD19 in the patient.
KYMRIAH (tisagenlecleucel CTL01) is a genetically modified product composed of autologous T cells that have been genetically modified with a lentiviral vector to produce a CAR consisting of a murine single-chain antibody (scFv) fragment that is specific to CD19, which is linked to an intracellular cytoplasmic domain for 4-1BB (CD13 and CD3 zeta) with a transmembrane hinge of CD8. The FDA and the EU have approved KYMRIAH for the treatment of pediatric patients and young adults up to 25 years of age with relapsed or treatment-resistant follicular lymphoma. Large B-cell lymphoma (LBCL) is a type of blood cancer that affects B cells, a type of white blood cell that produces antibodies. B-cell lymphomas are the most common type of non-Hodgkin lymphoma (NHL) and can be aggressive or indolent. BREYANZI (lysocabtagene maraleucel) is a type of gene therapy used to treat adult patients with LBCL who have failed to respond or who have relapsed after at least two other types of therapy.
It is a type of CAR T cell therapy in which the patient's own T cells are used to fight cancer. Acute lymphoblastic leukemia (ALL) is a devastating disease affecting adults. Fortunately, TECARTUS (brexucabtagene autoleucel), a gene therapy product, has been approved by both the U.S. Department of State and by the EU FDA to combat this disease.
Gene therapy has become a solid and versatile tool that can catalyze the advancement of personalized medicine, revolutionize the effectiveness of therapy and improve the side effects of commonly used drugs. The fastest evolution of personalized medicine is seen in the areas of treatment of cancer and inherited disorders, where gene therapy strategies and products play a fundamental role. However, the potential of gene therapy extends far beyond these fields and encompasses a wide range of pathologies, such as neurodegenerative diseases, immune disorders, inflammatory processes and more, that require further research. Despite notable advances, challenges remain in the practical use of gene therapy.
These include, but are not limited to, issues related to safety, specificity, efficacy of administration, and immune responses. For example, although viral vectors are highly effective, they can elicit immune responses. Non-viral vectors, while less immunogenic, are less effective. Balancing these contrasting attributes is a key concern. In addition, certain ethical, regulatory, and marketing challenges must be addressed for gene therapy to be more widely adopted.
Researchers embarking on the nascent phases of product development are faced with a multifaceted problem that encompasses current technological frontiers, product commercialization, and the potential for costly solutions. While some of these innovative solutions hold promise for transformation, their accessibility to patients may be limited by high costs. It is imperative that these pioneering business decisions be based on judicious foresight, as ill-conceived approaches could jeopardize not only production but also the integration of gene therapy products into medical practice. Given the potentially transformative impact of gene therapy, it's critical that these challenges be addressed with comprehensive and well-thought-out solutions.
Looking to the future, the field of gene therapy has immense potential. As our understanding of the human genome deepens and our tools for genetic manipulation become more sophisticated, the scope of gene therapy is likely to continue to expand. There is no doubt that continued research and innovation in this field will lead to more effective treatments and cures for a variety of diseases, transforming the lives of patients around the world. We hope that this review will provide researchers, clinicians, and policymakers with a full understanding of the current state of human gene therapy, and will serve as a launching pad for future advances in this promising field.
National Library of Medicine 8600 Rockville Pike Bethesda, MD 20894. NEWDIGS maintains a list of approved durable cell and gene therapies (CGT), including approval dates for new biological products and complementary indications. Durable cellular and genetic products are designed to be used only once, compared to products that are administered more than once. To celebrate the achievements of the scientific community and patients who are dedicated to cell and gene therapy, let's reflect on all cell and gene therapies approved by the FDA to date.
