Fig. 1.

Schematic representation of methods used to deliver gene therapy approaches directly into the CNS, in clinical and pre-clinical trials for ALS. Direct access to the central nervous system (CNS) is currently considered the best method for efficient delivery of gene therapy strategies for motor neuron disorders. To date, the preferred translational route of administration is the intrathecal (IT) delivery. This is a minimally invasive method and consents widespread distribution of gene therapies through the cerebrospinal fluid (CSF) and consequently to the CNS. Other two methods are currently investigated in pre-clinical studies for efficient access to the CSF: the intracerebroventricular (ICV) and intra-cisterna magna injections. Although these are easily applicable in experimental models (such as ALS mice), their translation to humans could be hard. Recently, the subpial injection was also reported as method allowing viral vector distribution to the spinal cord in animal models, including non-human primates. Further investigations are needed to define the best delivery route for efficient translation of gene therapy treatments to patients. The seek for non-invasive and efficient delivery methods, represent a key step for the future development of these innovative approaches.