{"id":6466,"date":"2023-12-07T14:00:46","date_gmt":"2023-12-07T03:00:46","guid":{"rendered":"https:\/\/rettaustralia.org.au\/?p=6466"},"modified":"2023-12-07T14:06:48","modified_gmt":"2023-12-07T03:06:48","slug":"fda-approval-for-the-neurogene-gene-therapy-strategy","status":"publish","type":"post","link":"https:\/\/rettaustralia.org.au\/blog\/fda-approval-for-the-neurogene-gene-therapy-strategy\/","title":{"rendered":"FDA approval for the Neurogene gene therapy strategy."},"content":{"rendered":"
Members of the Rett community were excited to learn that Neurogene received approval in January 2023 from the US Food and Drug Administration (FDA) to perform a Phase 1\/2 clinical trial in paediatric patients with Rett Syndrome. This allows the company to examine the safety and efficacy of gene replacement therapy by their product, named NGN-401. This is comprised of adeno-associated virus (AAV) that delivers a full-length copy of a functional MeCP2 gene. As FDA approval represents a highly significant step, it is useful to review pre-clinical data that were published recently and contributed to the FDA decision (S. Powers et al; Novel MeCP2 gene therapy is effective in a multicenter study using two mouse models of Rett Syndrome and is safe in non-human primates. Molecular Therapy, July 2023<\/em>).<\/p>\n Neurogene and other companies have used AAV (in this case AAV type 9) to deliver genes to neurons. It is necessary to use AAV because naked DNA i) is usually destroyed during delivery and ii) entry into any cell type, including neurons, is extremely poor. Although AAV is a small virus that limits the size of the DNA (gene) that can be packaged for delivery, it is currently the preferred vehicle for most applications of gene therapy (D Wang et al, 2019. Adeno-associated virus vector as a platform for gene therapy delivery. Nat Rev Drug Discov 18: 358-378<\/em>). The packaging limit was overcome by Taysha, another company which has already begun a Phase 1 trial in Rett patients, by using a MeCP2 minigene whereas Neurogene uses a different strategy, discussed below, to overcome packaging limitation.<\/p>\n It is necessary to remind the reader of the Central Dogma,<\/em> the fundamental manner in which proteins are expressed in human cells, a process in which the information contained in the DNA (gene) is transferred into messenger RNA (mRNA) then into protein, in this case, MeCP2. (See RSAA website; https:\/\/rettaustralia.org.au\/blog\/progress-towards-a-cure-for-rett-syndrome-by-rna-editing\/<\/a>). The production of mRNA is started by cellular proteins which recognise a region on the gene, termed the promoter; the MeCP2 promoter is large, compromising the ability of the AAV to package the MeCP2 gene. To overcome this, Neurogene previously used a promoter that comprised approx 70% of the full-length promoter but in this study (Powers et al, 2023) reduced this to 50% to ensure that the gene can be effectively packaged by the AAV, without loss of promoter activity. <\/p>\nThe MeCP2 gene and strategy used by Neurogene.<\/strong><\/h5>\n