Gene therapy

Gene therapy is the use of genes or genetic material to treat or prevent disease. Types of gene therapy include replacing a mutated gene with a healthy copy, inactivating or knocking out a mutated gene, and introducing a new gene to fight disease. Instead of delivering an entire gene, gene editing can deliver genetic material that edits DNA within a cell. In vivo gene therapy approaches directly introduce the gene therapy into the body. Ex vivo approaches in gene therapy first remove cells from the patient, and genetic modification occurs outside the body, followed by the reintroduction of cells back into the patient. RNA-based and RNA-targeted therapeutics, such as siRNA and antisense oligonucleotides, are considered gene therapy.

Most gene therapies use a viral vector to deliver genetic material into cells.

Adeno-associated viruses (AAVs) are the most popular delivery systems for gene therapy in clinical trials as of 2022. Early- and late-stage clinical trials for hemophilia, inherited blindness, and muscular dystrophy have been successful in terms of safety and efficacy. AAVs are non-pathogenic, have low immunogenicity, infect a broad range of cell types, and are able to achieve efficient and long-lived gene transfer.

AAV was originally discovered as a contaminant in simian adenovirus preparation and was later found to integrate into the host genome during the latent state of the viral life cycle. For productive replication, AVV relies on co-infection with a helper virus, such as adenovirus or herpes virus. For gene transfer applications, the gene of interest is inserted into replication-defective AAV viral-like particles (recombinant AAV or rAAV) in which viral open reading frames have been removed.

One challenge for AAV vector-based gene therapies is pre-existing humoral immunity to AAV capsids, antibodies to AAV present due to exposure to wild-type AAV, which are common in the environment. Patients are often excluded from clinical trials due to pre-existing neutralizing antibodies that might reduce transduction efficiency. Other challenges include poor transduction efficiency in certain tissues and low organ specificity, and patients show vector dose-dependent toxicity. The high cost of production of rAAV is also an obstacle to its use in gene therapy.

CRISPR-Cas9 is an RNA-guided genome editing tool, first used in mammalian organisms in 2013, that has become a cost-effective and convenient tool for gene therapy applications. CRISPR-Cas9 can be used to correct disease-causing mutations or engineer pathogens such as HIV for therapeutic purposes or introduce protective or therapeutic mutations.

A CRISPR/Cas9-based strategy, termed homology-independent targeted insertion (HITI), enables targeted gene insertion in non-dividing cells, both in vitro and in vivo. This technique was developed to overcome a barrier to gene therapy in that many technologies are not able to target non-dividing cells such as neurons.

The majority of gene therapies in clinical trials between 2010 and 2020 were for the treatment of cancer. Ex-vivo gene therapy is an approach to developing immunotherapy. CAR T-based immunotherapies are generated by engineering T cells to express chimeric receptors on their surface, allowing them to react to specific molecules such as tumor-associated antigens.

• Luxterna—FDA and Health Canada approved in-vivo AAV (Adeno-associated virus) gene therapy product for Leber congenital amaurosis (LCA).

• Abecma—CAR-T cell therapy for multiple melanomas
• ARI-0001—CAR-T therapy approved by the Spanish Agency for Medicines and Health Products (AEMPS) for acute lymphoblastic leukemia
• Breyanzi—CAR-T therapy for large B cell lymphoma
• Carteyva—CAR-T therapy approved by the China National Medical Products Administration (NMPA) for large B cell lymphoma and follicular lymphoma
• Carvykti—CAR-T therapy FDA-approved for multiple myeloma
• Kymriah—FDA-approved CAR-T therapy for B cell acute lymphoma and follicular lymphoma
• Tecartus - FDA—approved CAR-T therapy for refractory B-cell precursor acute lymphoblastic leukemia
• Yescarta—FDA-approved CAR-T therapy for large B-cell lymphoma and follicular lymphoma

• Oncolytic viruses are genetically engineered or naturally occurring viruses that selectively replicate in and kill cancer cells and do not harm normal tissues.
• Delytact—Conditional approval in Japan for oncolytic virus therapy for brain cancer; the product is a triple-mutated, replication-conditional herpes simplex virus type 1 (HSV-1)
• Imlygic—FDA-approved engineered human herpes simplex virus (HSV) as an oncolytic virus to treat advanced melanoma
• Oncorine—Oncolytic virus approved in China, indicated for nasopharyngeal carcinoma
• T‐Vec—Approved in USA and Europe, oncolytic herpes simplex virus type 1 (HSV‐1) with the gene GM‐CSF to treat melanoma

• Gendicine—Approved in China, recombinant human p53 adenovirus for head and neck cancers

• Amondys 45—Exon skipping therapy for Duchenne muscular dystrophy (DMD)
• Viltepso (Nippon Shinyaku)—Approved in Japan and the US, exon 53 skipping antisense oligonucleotide indicated for the treatment of Duchenne muscular dystrophy (DMD)
• Vyondys 53 (Serepta Therapeutics)—FDA-approved exon 53 skipping antisense oligonucleotide indicated for the treatment of Duchenne muscular dystrophy (DMD)

• Leqvio—Approved in the UK and US to treat high cholesterol, small interfering RNA (siRNA) given by subcutaneous injection that reduces low-density lipoprotein cholesterol

• Collategene—Approved in Japan, plasmid DNA encoding human hepatocyte growth factor to treat critical limb ischemia

• Invossa—Was approved in Korea and later suspended; for treatment of knee osteoarthritis

• Neovasculgen—Approved in Russia for peripheral artery disease

• Givlaari—FDA-approved to treat acute hepatic porphyria (AHP)
• Libmeldy—Approved in the UK to treat metachromatic leukodystrophy (MLD)
• Onpattro—RNAi therapeutic approved in the United States and Canada for cardiomyopathy and polyneuropathy due to transthyretin-mediated (ATTR) amyloidosis
• Oxlumo—FDA-approved RNAi therapeutic for the kidney disease, primary hyperoxaluria type 1 (PH1)
• Skysona—FDA-approved, ex vivo transduction of functional ABCD1 genes with the Lenti-D lentiviral into the patient's hematopoietic stem cells for the treatment of cerebral adrenoleukodystrophy (CALD)
• Stremvelis—EMA-approved, used ex vivo to treat combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID)
• Tegsedi—FDA-approved antisense oligonucleotide inhibitor of the transthyretin (TTR) protein for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis
• Waylivra—EMA-approved, antisense oligonucleotide apolipoprotein C-III (ApoC-III) inhibitor used to treat familial chylomicronaemia syndrome (FCS)
• Zolgensma—FDA-approved SMN1 DNA delivered via AAV vector gene therapy indicated for pediatric spinal muscular atrophy (SMA)
• Zynteglo—FDA- and EMA-approved, autologous hematopoietic stem cells transduced ex vivo with lentiglobin BB305 lentiviral vector encoding the β-globin gene derivative (βAT87Q-globin) for treatment of ß-thalassemia