Gene Therapy

Gene therapy is a therapeutic approach to genetic disease that delivers a functional copy of the aberrant gene in vivo, an intuitive solution that has taken 3 decades to reduce to clinical practice, predominantly using adeno-associated viral vectors. ^[1] There are an estimated 8,000 genetic disorders that cumulatively affect approximately 10% of the population, and even among the 5% of patients with genetic disease who have treatment options, those therapeutics rarely address the underlying cause and typically require recurrent, lifelong therapy. ^[1] Gene therapy can be performed in vivo, delivering therapeutic genes directly into the target tissues or cells of patients, or ex vivo, modifying cells extracted from the patient and then reintroducing the transgene-expressing cells. ^[2] The strategies in clinical and preclinical use include gene replacement, gene silencing and gene editing, with gene replacement suited to recessive monogenic diseases and responsible for most clinical success so far. ^[3] Gene therapy is also being developed for non-hereditary age-related conditions such as neovascular age-related macular degeneration, where the aim is a single durable treatment in place of repeated intravitreal anti-VEGF injections. ^[4]

Delivery depends on a vector, and the three most widely used viral vectors are lentiviruses, adenoviruses and adeno-associated viruses, alongside non-viral systems such as lipid nanoparticles and N-acetylgalactosamine conjugates that have also yielded approved products. ^[2] Adeno-associated virus vectors are predominantly non-integrating, forming extrachromosomal episomes in the nucleus with the potential for long-term gene expression. ^[1] With integrating vectors the viral DNA integrates into the host genome so that the gene is passed on during cell division, which provides long-term stable expression but makes insertional mutagenesis the most significant risk. ^[2] In haemophilia, a single infusion of a modified adeno-associated virus delivers the factor VIII or factor IX gene to the liver, leading to continuous endogenous synthesis and secretion of the missing coagulation factor by the hepatocytes. ^[5] Beyond gene addition, base editors and prime editors enable precise single-base changes or small insertions without generating double-strand breaks, reducing the risk of unintended genomic rearrangements compared with conventional CRISPR-Cas9. ^[6] In aging research the same platforms are used to modulate aging-regulatory pathways such as epigenetic regulation

Voretigene neparvovec-rzyl (Luxturna) was cleared by the US Food and Drug Administration in December 2017 for confirmed biallelic RPE65-mediated inherited retinal disease and represented the first FDA-approved gene therapy for an inherited disease. ^[7] Onasemnogene abeparvovec (Zolgensma), an adeno-associated virus serotype 9 therapy, was approved in 2019 for type I spinal muscular atrophy, the most common single-gene disease causing infant mortality. ^[2] Delandistrogene moxeparvovec, the first approved gene therapy for Duchenne muscular dystrophy, received initial accelerated approval in 2023 and full approval in 2024 for ambulatory patients, with accelerated approval continued for non-ambulatory patients, although its long-term efficacy, durability and safety remain unconfirmed. ^{[1] [8]} A total of 14 ex vivo and 21 in vivo vector-based gene therapies have been granted market approval, primarily by the US Food and Drug Administration. ^[2] Approval is not irreversible: Glybera, the first adeno-associated virus gene therapy approved in Europe, was withdrawn from the market in 2017 because of its ineffectiveness, difficulty of administration and a lack of patients. ^[2] In severe haemophilia, adeno-associated virus-mediated gene transfer has raised and in some cases transiently normalised factor VIII or factor IX activity in adults, and raising levels to greater than about 15 IU/dL corresponds to a marked decrease in bleeding, a dramatic reduction in factor concentrate use and improved quality of life.

Pre-existing neutralising antibodies against the vector capsid reduce transduction and can limit eligibility, and the prevalence of anti-AAV8 neutralising antibodies in the human population ranges from 10% to 40% depending on geographical sampling. ^[3] Although adeno-associated virus has lower immunogenicity than other viruses, at high doses it can still trigger severe immune reactions including hepatotoxicity, complement activation and acute kidney injury. ^[2] In haemophilia gene therapy an asymptomatic, self-limiting, immune-mediated rise in alanine aminotransferase is commonly observed within the first 12 months after gene transfer and has the potential to eliminate the transduced hepatocytes unless treated with immunosuppressive agents such as corticosteroids. ^[5] In Duchenne muscular dystrophy, immune-mediated toxicities including myositis, myocarditis and liver injury present significant clinical challenges and prompt the need for careful patient selection, immunoprophylaxis and post-treatment monitoring. ^[8] The first death related to delandistrogene moxeparvovec was announced in March 2025, in a 16-year-old non-ambulatory male, secondary to acute liver failure presenting around 9 weeks after gene transfer. ^[1] A clinical trial of gene therapy for myotubular myopathy using an AAV8 vector reported deaths in the high-dose group, reiterating the need to manage vector dose carefully for safety as well as efficacy.