Current list of FDA approved Gene Therapies*
Current list of FDA approved Gene Therapies*
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Spinal mascular atrophy (SMA) - SMN1 gene
Spinraza is the first ever FDA-approved gene therapy. It is an antisense oligonucleotide (ASO). Individuals with SMA diagnosis bare an autosomal recessive variant of the SMN1 gene. In healthy individuals, the SMN1 gene produces the SMN protein, which is crucial for motor neuron survival. In diseased patients, due to the mutation in the SMN1, the SMN protein is not produced in the active form in contrast to healthy individuals. Interestingly, there is another gene known as SMN2, which produces a truncated version of SMN protein, which is unstable in both healthy individuals and patients with SMN1 mutation. This SMN instability from SMN2 is due to the fact that during splicing the exon 7 is being excluded in SMN translation. Elegantly designed ASO attaches between exon 7 and 8 and prevents exon 7 deletion via splicing modulation, resulting in SMN2 gene producing a functional and stable SMN protein.
A few years later, in 2019, another medication for SMA - Zolgensma - came to the market. In this case, it only requires a one-time administration, in contrast to multiple scheduled administration of Spinraza. This became possible due to the fact that Zolgensma consists of an AAV9 capsid, carrying a full SMN1 transgene with a promotor. The capsid delivers a fully functional gene copy to motor neurons, where the transgene is further translated into the SMN protein.
Leber congenital amaurosis (LCA) - RPE65 gene
In December 2017 a breakthrough in inherited retinal degenerations happened - the first ever gene therapy in ophthalmology was approved for clinical use. This medication is certified for one very rare form of inherited retinal dystrophy known as Leber congenital amaurosis type 2 with a mutation in RPE65 gene. LCA2 is an autosomal recessive disease, one of the most severe forms of inherited retinal dystrophies, which is characterized by a very early disease onset (first months of life) and severe vision loss, nystagmus at birth and light sensitivity. Human retina consists of 10 morphologically distinct layers, where the outermost layer consists of a monolayer of retinal pigmented epithelial cells, followed by the layer of photoreceptors (rods and cones). In healthy population RPE65 is expressed in RPE cells and encodes a retinoid cycle enzyme - retinoid isomerohydrolase. This protein regenerates 11-cis retinal, which is an essential component of the phototransduction pathway in photoreceptor cells. RPE65 was chosen as a first IRD target, due to the great morphological preservation of the RPE und photoreceptor cells in the retina, allowing for functional recovery of the missing protein machinery.
Luxturna is composed of a AAV2 capsid with functional cDNA for RPE65 gene and is delivered via a subretinal injection. The capsid transducts retinal pigmented epithelial cells with an RPE65 transgene. Functional RPE65 protein allows for preserving/regenerating the function of photoreceptors and their response to light.
Hemophilia B - FIX gene
Hemophilia is a disease which is characterized by excessive bleeding due to the blood clotting defect. Mutation in the FIX (Factor IX) gene is responsible for Hemophilia B. In the general population this gene produces the blood clotting factor 9, which is an important regulator in coagulation cascade. Through activation of Factor X and Thrombin it converts Fibrinogen to Fibrin resulting in the formation of a blood clot.
The first ever gene therapy Hemgenix for a treatment of a severe X-Linked recessive bleeding disorder Hempophilia B was approved by FDA in 2022, followed by Beqvez in 2024.
Hemgenix is an AAV5 based therapy, carrying the FIX gene. The AVV targets hepatocytes (liver cells), where it releases the episomal transgene - a gene that does not integrate into the host genome but exists as a separate genetic unit. Liver cells then transcribe and translate the FIX gene into the Factor IX protein, resulting into the functional coagulation cascade.
Beqvez has essentially the same mechanism of action. It was discontinued by Pfizer in February 2025, due to low demand.
Hemophilia A - FVIII gene
Same as Hemophilia B, Hemophilia A is an X-linked recessive diseases, which occurs almost exclusively in males, and is characterized by the absence of clotting Factor VIII (FVIII). The lack of factor VIII protein hinders the activation of Factor X and eventual Fibrin formation resulting in the uncontrollable bleeding. See the coagulation cascade diagram here.
Roctavian is AAV5 based therapy. Due to the large size of the Factor VIII gene and associated with this packaging challenges, the vector carries a cassette with the truncated version of the Factor VIII gene, where the B-Domain is deleted. The cassette is inserted between two AAV 2 inverted terminal repeats (ITRs). The cassette also contains hepatocyte specific promotor, consisting of a truncated ApoE Hepatic promoter region with a alpha-1-anti-trypsin promotor.
While this little review was in preparation, a new therapy - Fitusiran was approved in March 2025 for both Hemophilia A and B. This elegantly designed drug is a small interfering RNA (siRNA) molecule which attaches to the Antithrombin mRNA and degrades it. In the coagulation cascade Antithrombin inhibits the formation of Thrombin and thus prevents eventual Fibrinogen conversion to Fibrin, suppressing blood clot formation. Fitusiran blocks the translation of Antithrombin protein, which improves blood clotting even in the absence of Factor VIII or IX. This medication is administered subcutaneously in multiple doses. And what is the most exciting - this is the first siRNA-based therapy! - it was my very first gene editing tool to learn in the lab as a Master student to silence the αVβ5 Integrin in the eye lens.
Sickle cell disease (SCD) - HBB gene
Sickle cell disease (SCD) is the most lethal monogenic blood disorder involving Hemoglobin production. Hemoglobin, an oxygen carrying protein, consists of two α-globin subunits and two ß-globin subunits. SCD occurs due to a single base-pair point mutation in the ß-globin gene (GAG to GTG). This results in the amino acid substitution (Glutamic acid to Valine at position 6) in the corresponding ß-globin chain of Hemoglobin. This Hemoglobin is referred to as a Hemoglobin S (HbS). In the deoxygenated environment red blood cells (RBC) containing HbS polymerize and become rigid. These rigid RBCs lead to vascular occlusions, local ischemia and increased hemolysis. Despite its very certain genetical background SCD has variable clinical phenotypes with symptoms including acute generalized pain, strokes, hemorrhages, varying from very mild presentation to very severe.
Lyfgena and Casgevy were both approved for SCD treatment at the end of 2023. Casgevy approval was a historical event in gene therapy development as this is the very first (and hitherto the only) CRISPR-Cas9 based therapy, and is also approved for the treatment of ß-thalassemia. Lyfgenia works on the basis of a lentiviral vector.
CRISPR-Cas9 is a method to edit DNA, which was discovered based on a naturally occurring defense mechanism in bacteria against viruses. This mechanism was modified and adapted to change DNA in other systems, including human genome. The system consists of a Cas9 protein - a nuclease which functions as "molecular scissors" and introduces a double-stranded DNA cut, - and a guiding RNA molecule which is designed to find and deliver Cas9 to a complementary site of interest on the DNA. One could mistakenly assume that Casgevy edits the mutation in the ß-globin gene and solves the problem, but that's not the case. In fact, human genome is designed to produce two different forms of Hemoglobin - adult Hemoglobin (HbA) and fetal Hemoglobin (HbF). The latter has a higher affinity to oxygen, is being produced during fetus development and slowly decreases after birth. Casgevy modifies the transcription factor BCL11A, which normally suppresses the HbF production, specifically the γ-globin subunit, in adults. This allows to produce more of HbF which compensate the function of HbA. The CRISPR-Cas system is delivered to RBCs via electroporation.
Lyfgenia is a lentiviral vector (LVV) based therapy. Lentiviruses are type of retroviruses, meaning they carry a single stranded RNA molecule with a reverse transcriptase enzyme, which catalyzes the transcription of RNA to cDNA. One example of a Lentivirus is Human immunodeficiency virus (HIV). Lentiviruses are known to be able to infect both, dividing as well as non-dividing cells, thus allowing lentiviral vectors to be used in such systems as neuronal tissue where cell division is minimal. Lyfgenia is a LVV that carries an RNA sequnce of a modified version of ß-globin transgene, resulting in the production of a modified HbA (HbAT87Q ). The modified adult HbA is specifically designed with a single amino acid substitution, providing such a chemical structure, which not only carries the function of the adult hemoglobin, but also inhibits expression and polymerization of HbS.
Both, Casgevy and Lyfgenia therapies involve an autologous transplantation of the CD34+ stem and progenitor cells. Additionally, patients undergo chemotherapy treatment known as myeloablative conditioning to eliminate the rest of the stem cells carrying the mutation from the bone marrow.
Duchenne muscular dystrophy (DMD) - DMD gene
Duchenne muscular dystrophy is a disease which predominantly affects males, due to its X-linked recessive pattern of inheritance. It is caused by a mutation in DMD gene, which encodes a Dystrophin protein.
DMD gene is the largest in the human genome, containing 79 exons and 2.6 billions base pairs ! If you ever went through the pain of trying to understand and remember muscle molecular physiology, you will probably want to skip the pathogenesis part of DMD anyway. For those of you still full of enthusiasm, I do my best, to squeeze it into two sentences.
In the myocytes, Dystrophin binds to multiple proteins forming a Dystrophin-associated protein complex. This complex connects the cytoskeleton to the extracellular matrix, providing mechanical stability during muscle contraction. In DMD, the absence of Dystrophin disrupts this linkage, leading to increased membrane fragility, calcium influx, and subsequent muscle cell damage.
Elevidys uses a modified AAV vector with high affinity to muscle cells. The vector delivers the transgene, encoding a shorter version of the dystrophin (as the whole dystrophin gene would obviously be too big to pack into the vector) known as micro-dystrophin, to the myocytes. This micro-dystrophin has been shown to be able to rescue the phenotype and slow the disease progression. Additional specificity of the therapy is assured by a muscle specific promotor, which is a modified version of a muscle tyrosine kinase (MHCK7).
While a few other therapies, such as Viltepso and Vyodinis, were approved for the DMD under the accelerated program, continued approval is contingent on further clinical trials demonstrating a benefit in disease progression. These therapies are antisense oligonucleotides, which bind to exon 53 of dystrophin pre-mRNA, resulting in exclusion of this exon during mRNA processing and allowing for production of an internally truncated dystrophin protein.
ß-thalassemia - HBB gene
Beta-Thalassemia is an autosomal recessive blood condition which can occur due to various mutations in beta-globin (HBB) gene. HBB is also involved in development of SCD. The difference between two conditions is that SCD develops due to a single point mutation and resulting faulty function of Hemoglobin, while in ß-thalassemia, the beta-globin synthesis is significantly reduced or absent, hindering the production of Hemoglobin and resulting in alpha- and beta-globin chain imbalance. Patients who carry the diseased mutation or deletion of this gene develop hemoglobinemia and related to it symptoms with a high clinical variability (from no symptoms to sever anemia).
Zynteglo, same as Lyfgenia for SCD, is a lentiviral vector based therapy which carries an RNA, encoding for a modified version of HBB with Threonine to Glutamine amino acid substitution at position 87 (T87Q). Like described before, this therapy is applied as a part of autologous transplantation targeting CD34+ stem and progenitor cells.
Dystrophic epidermolysis bullosa - COL7A1 gene
Is the first topical gene Therapy approved by FDA. The gel is applied to the wounds of patients over 6 months old with a confirmed COL7A1 mutation. COL7A1 gene is responsible for production of collagen type VII. Individuals with this mutation develop painful blisters and wounds on the skin, as well as secondary symptoms. Interestingly, other types of collagen mutations, such as COL2A1, COL11A1, COL11A2, COL9A1 and COL9A2, are responsible for the development of Stickler-Syndrom, which has multiple ocular manifestations, including retinal detachment.
The treatment of dystrophic epidermolysis bullosa is based on live, replication deficient Herpes simplex virus type 1 (HSV-1) vector, which carries the a functional COL7A1 transgene. Vyjevek transduces both keratinocytes and fibroblasts and delivers a vector genome episomaly into the nucleus. There the transcription of the COL7 protein is initiated, and results in the formation of long bundles knowns as anchoring fibrils. These anchoring fibrils hold epidermis and dermis together, ensuring skin integrity. Interestingly, the clinical trial also showed the benefit of the beremagene geperpavec for treatment of the corneal defects of DEP patients.
Literature:
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)31868-8/fulltext
https://link.springer.com/article/10.1007/s40265-023-01921-5
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*this list does not include gene editing drugs which are combined with cell therapies, or gene editing therapies approved under the accelerated program
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