What are the gene therapies?
Following Stanfield Rogers’s 1970 discovery of using “good” deoxyribonucleic acid (DNA) to replace faulty DNA in hereditary disorders, the idea of gene therapy for human diseases was clearly advanced by Theodore Friedmann and Richard Roblin as early as 1972. Gene therapy has the potential to regulate defective genes, therefore treating the underlying causes of monogenic illnesses and other genetically specified diseases. Gene therapy was described by the United States Food and Drug Administration (FDA) as a method that alters a person’s genes in order to treat or cure disease. The FDA said that gene therapy could work in three ways: first, by substituting a healthy gene for a disease-causing one; second, by rendering a disease-causing gene inactive if it was not functioning correctly; and third, by introducing a new or altered gene into the body to aid in the treatment of a disease. Human gene therapy, according to the FDA’s definition, aims to change the biological characteristics of live cells or modulate gene expression for therapeutic purposes. The pharmaceutical items authorized for use in gene therapy for the purposes of treatment, prevention, or diagnostics were known as gene therapy medications, and they were a game-changer in the pharmaceutical and health sciences industries. Biological medical products that were supplied as viruses, lipid complexes, nucleic acids, or genetically altered micro-organisms for diagnostic, preventive, or therapeutic purposes were also known as gene therapy medications.
FDA-approved gene therapy drugs
Worldwide, there have been more than 2,000 documented human gene therapy clinical studies, and 20 gene therapy products have already received approval. With these new developments, there is renewed optimism that we can find a cure for incurable diseases and those that are extremely uncommon and terrible. Markets throughout the world are seeing a dramatic shift as a result of advances in our knowledge of disease pathomechanisms and our ability to target and deliver genes with pinpoint accuracy.
Antisense oligonucleotides (ASO): Antisense oligonucleotides, which are complementary to the sense strand of nucleic acids, are typically short (15-30 bp in length), synthetic, single-stranded oligodeoxynucleotides capable of modifying mRNA and regulating protein production to inhibit disease processes.
For intravitreal injection-based local therapy of CMV retinitis in immunocompromised individuals, the first antisense oligonucleotide medication, Vitravene (Fomivirsen), was authorized for sale by the FDA in 1998 and the EMA in 1999. Vitravene’s DNA sequence was found to be complementary to a sequence in mRNA transcripts that code for the primary immediate early region 2 of the human coronavirus.
For the treatment of Duchenne muscular dystrophy in individuals with a verified DMD gene mutation that was compatible with exon 51 skipping, the FDA authorized Exondys 51 (Eteplirsen) in 2016. Mutations in the DMD gene, which encodes the functional dystrophin protein, produced X-linked recessive condition Duchenne muscular dystrophy (DMD). Skeletal and heart muscles progressively deteriorated due to a dystrophin protein deficiency. The goal of creating Exondys 51 was to cause exon 51 skipping in dystrophin pre-mRNA, which would restore creation of a partially functional dystrophin protein that was internally truncated.
The first medicine ever authorized for the treatment of spinal muscular atrophy (SMA) was Nusinersen, which Biogen marketed as Spinraza. Nusinersen received approval from both the FDA in December 2016 and the EMA in May 2017. One ASO, Nusinersen (Spinraza), modifies alternative splicing by enhancing the inclusion of exon 7 in the final processed RNA by targeting intron 7 on the SMN2 hnRNA. The consequence is an increase in the amount of functional SMN protein in the CNS. Lumbar punctures are performed under the close observation of a healthcare provider when intrathecal administration of Nusinersen is carried out. Motor neurons, vascular endothelial cells, and glial cells in the central nervous system (CNS) receive Nusinersen after injection. Patients with SMA who took part in several clinical studies found Nusinersen to have a satisfactory safety and tolerability profile. High amounts of protein in the urine and problems with the respiratory system were the most common side effects of the medication. In addition, while intrathecal administration is essential for motoneurons, it does not address other organ problems in SMA patients’ hearts, livers, pancreas, intestines, or lungs. Therefore, it is necessary to search for an ideal therapeutic that can restore SMN protein in peripheral tissues.
A non-viral vector loading RNAi drug: The first RNAi medicine produced globally was Onpattro (patisiran) by Alnylam Pharmaceuticals. In adults, Onpattro has received approval from both the FDA and the EMA to treat hATTR polyneuropathy in individuals with either stage 1 or stage 2 of the condition. There was a decrease in blood TTR protein and TTR protein deposits in tissues because Onpattro included a synthetic siRNA that led to the destruction of mutant and wild-type TTR mRNA through RNAi.
Viral vectors: Gendicine (recombinant human p53 adenovirus particle) contains the Tp53 gene and has been created for the treatment of head and neck squamous cell cancer (HNSCC). This recombinant adenovirus was received approval from the China Food and Drug Administration (CFDA) on October 16, 2003, subsequently entering the commercial market in 2004. Between 2003 and 2012, a total of 16 human clinical trials were conducted for the treatment of advanced stages and grades of head and neck cancer, malignant glioma, ovarian cancer, and hepatocellular carcinoma. Treatment with Gendicine yielded a superior overall response and increased survival rate relative to control groups.
Luxturna was a recombinant adeno-associated virus type 2 (rAAV2) vector genetically engineered to express the human retinal pigment epithelium-specific protein 65 kDa (RPE65) protein. It obtained approval from the FDA in 2017. Luxturna was administered into the subretinal space, resulting in the transduction of some retinal pigment epithelial cells to produce the RPE65 protein, hence offering the possibility of restoring the visual cycle in individuals with verified biallelic RPE65 mutation-associated retinal dystrophy.
A live, attenuated HSV type 1 vector called Imlygic (Talimogene Laherparepvec) was engineered to express human GM-CSF. Intratumoral injection of Imlygic allowed it to proliferate within tumors, which then generated the immune stimulatory protein GM-CSF. When tumors are lysed by Imlygic, antigens originating from the tumors are released. This, in conjunction with the expressed immune stimulatory protein GM-CSF, may enhance an immune response that targets cancers. For patients with recurrent melanoma following first surgery, Imlygic was authorized for the local treatment of unresectable cutaneous, subcutaneous, and nodal lesions. It is worth noting that this is the only oncolytic virus that has so far been licensed by the FDA and EMA.
With its 2010 FDA clearance, Rexin-G (Mx-dnG1) became the first targeted injectable gene therapy vector for the treatment of metastatic tumors. It encoded a cytocidal mutant dominant-negative cyclin G1 (dnG1) gene and was an amphotropic retrovector with a collagen-binding domain on its surface membrane that targeted aberrant Signature proteins in tumor tissues. By attaching to exposed collagenous proteins, Rexin-G may build up in malignant lesions after an intravenous injection, and then it could secrete the cytocidal dnG1 protein, which would stop the tumors from growing and spreading.
Aptamer: Pegaptanib, marketed under the Macugenis brand name, was developed by Eyetech Pharmaceuticals and Pfizer Inc. Neovascular age-related macular degeneration (AMD) can be treated with this polynucleotide aptamer, which targets the vascular endothelial growth factor (VEGF165 isoform). The sole medication for AMD at the time, pegaptanib, was authorized by the US FDA in December 2004 and was the first anti-angiogenic drug. Additionally, it has achieved FDA market clearance as the first medicinal aptamer having an RNA structure. Pegaptanib consists of two branched 20-kD polyethylene glycol chains covalently attached to an RNA oligonucleotide of 28 amino acids. The heparin binding site binds selectively to the VEFG165 isoform, blocking its ability to attach to the VEFG receptors on the surface of vascular endothelial cells. Because it increases inflammation and vascular permeability, VEFG165 may have a role in pathogenic ocular neovascularization. Pegaptanib, at a dosage of 0.3 mg/90 µl, should be injected intravitreal into the eye once every six weeks. Pegaptanib is metabolized via endonucleases and exonucleases, rather than the cytochrome P450 system, according to preclinical evidence. The effectiveness of Pegaptanib was assessed in two clinical studies with a total of 1,118 participants. The effectiveness was defined as the capacity of patients to maintain visual acuity levels below 15 letters from baseline, without any dose-response relationship. The outcome proved that Pegaptanib is a viable treatment option for AMD. In addition, 23 patients with neovascular AMD and a history of arterial thromboembolic events (ATEs) were studied in a clinical trial to determine the effectiveness and safety of Pegaptanib. Systemic or ocular side effects, as well as recurrent ATEs, were not observed in patients treated with pegaptanib.
References
- Shahryari A., et al., Development and clinical translation of approved gene therapy products for genetic disorders, Frontiers in genetics, 2019, 10: 868.
- Ma C C., et al., The approved gene therapy drugs worldwide: from 1998 to 2019, Biotechnology advances, 2020, 40: 107502.
- Mullard A. FDA approves first gene therapy for Duchenne muscular dystrophy, despite internal objections, Nat Rev Drug Discov, 2023, 22(8): 610.