Genetic Manipulation for Inherited Neurodegenerative Diseases - Myth or Reality? (.pdf)

The genetic revolution of the past 25 years has transformed our understanding of the genetic basis of human neurodegenerative diseases. The causative genes for a large number of well-recognised clinical entities have been identified and the pace of discovery will only accelerate further as next-generation whole-genome sequencing becomes routinely available to clinicians. In addition to classical monogenetic diseases with high penetrance, it is now clear that the majority of common late-onset neurodegenerative disorders are heavily determined by a complex cluster of genetic variants, each contributing to the overall risk of developing overt clinical disease, and in some cases having a synergistic deleterious interaction with environmental triggers. Unfortunately, the significant advances made in deciphering the genetic factors that contribute to the underlying neuropathological process have so far resulted in limited therapeutic benefits for patients. A number of factors have contributed to this frustrating translational gap and the challenges that remain are daunting. This review will provide a critical overview of genetic strategies that are being pioneered to halt or reverse disease progression in inherited neurodegenerative diseases. This field of research covers a vast area and only the most promising treatment paradigms will be discussed with a particular focus on inherited eye diseases, which have paved the way for innovative gene therapy paradigms, and mitochondrial diseases, which are currently generating a lot of debate centred on the bioethics of germline manipulation.