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After a roller-coaster ride of hype and disappointment, the decades-long effort to cure diseases by repairing or replacing faulty genes is starting to yield useful treatments. Diseases that have defied treatment could be reversed by a one-time fix to a faulty gene.
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Gene therapy for single-gene disorders is at a pivotal period in its evolution, with continued successful development requiring tight collaboration among industry, academic, regulatory, clinical and patient communities.
A glutamate-gated chloride channel delivered via gene therapy is shown to detect elevated brain glutamate levels and trigger the suppression of neuronal excitability, thereby attenuating seizure activity in two rodent models of epilepsy.
Patients with junctional epidermolysis bullosa (JEB) carry mutations in genes that encode components of the basement membrane, which ensures the integrity between the epidermis and the dermis, such as laminin-332. These mutations cause blistering of the skin and chronic wounds. Following initial treatment of an adult patient with a limited affected region, Michele De Luca and colleagues reconstruct the full epidermis of a 7-year-old patient with autologous transgenic cells transduced with a virus vector carrying the non-mutated form of laminin-322. The integration sites of the virus used for gene delivery provide a tracing tool ex vivo and in vivo and demonstrate that the human epidermis is sustained by a limited number of long-lived stem cells.
In utero GBA gene therapy extends lifespan and provides long-lasting phenotypic amelioration in a mouse model of neuronopathic Gaucher disease. Fetal ultrasound-guided in utero gene vector delivery is also achieved in the non-human primate brain.
The potential of adeno-associated viral (AAV)-mediated gene therapy for neurological disorders is rapidly emerging. Evidence of clinical efficacy and safety, as well as durable transgene expression, has now been reported in several central nervous system disorders. Here, Sah and colleagues discuss key considerations in the design and development of therapeutic AAV vectors, highlighting promising therapeutic targets and recent clinical trials.