Start Making Sense - Exon Skipping & Nonsense Suppression
A joint revolution in the treatment of genetic disease?
Twenty-two years ago, the largest gene found in nature was isolated, and a year later it was sequenced. This 2.4Mb leviathan encoded no mere housekeeping protein - its 3685-amino-acid product, a rod-shaped human muscle protein now known as dystrophin, is of profound significance to families affected by the various forms of muscular dystrophy, a disease which occurs in 1 in 3500 newborn males. Mutations in the encoding gene can result in a whole spectrum of phenotypes, from in-frame minor mutations which can lead to the relatively benign Becker muscular dystrophy (BMD), to out-of-frame mutations and premature stop codons, which result in expression of non-functional dystrophin and the much more severe Duchenne muscular dystrophy (DMD), which is characterized by progressive deterioration of muscle tissue and generally proves fatal by the age of 30. At the time this gene was sequenced, this event was hailed as a landmark, paving the way for the design of therapeutics for a previously-incurable disease - the science of gene therapy was in its infancy and as is all too common following such breakthroughs, a cure via gene replacement seemed within reach in just a few years.
However, 22 years on, the slow progress of gene therapies to market has been profoundly disappointing in all sectors, not only for muscular dystrophy or other genetic diseases - as yet, following a quarter of a century of frenetic R&D activity, there are still only two gene therapies launched worldwide, and both of these are for cancer (Gendicine in China and Rexin-G in the Philippines). Replacing (or rather augmenting) expression of a mutated sequence with a healthy one may be straightforward enough in the laboratory, but the major problem over the years seems to have been in expressing sufficient levels of the wild-type (healthy) protein in the target tissue for a long enough period to achieve a significant therapeutic effect. The frustration has been reflected across other monogenic disorders - even for conditions where marketed protein replacement therapies already exist, such as haemophilia-A and -B and the lysosomal storage disorders, such as Gaucher's and Fabry's diseases. In the previous flagship field of cystic fibrosis, commercial gene replacement therapy R&D activity has dwindled over the years from 12 active projects in 1999 (of which 4 had reached Phase II trials) to a virtual absence of gene therapy activity at present, and a refocus on symptomatic treatments. Regarding muscular dystrophy, the number of gene replacement therapy projects has fallen to just four, all early-stage.
