As highlighted by Dr Stuart Nicklin’s post in April this year, scientists are working on developing new, more powerful adeno-associated vectors (AAVs) to improve their spread throughout brain. This is important for central nervous system (CNS) diseases but also other diseases like lysosomal storage disorders (LSDs) with CNS defects. Tordo et al (2018) now report the development of a novel AAV that was used to treat Sanfilippo type C, a rare LSD with neurological symptoms. This study gives hope to find more potent AAVs that can be used for CNS diseases in the future.
Lysosomal storage disorders (LSDs) are a group of more than 50 inherited disorders that are characterised by the accumulation of storage or waste material in the lysosome. Most LSDs show neurological symptoms and are caused by defects in soluble lysosomal enzymes. The development of AAV gene replacement therapies for these types of LSDs is facilitated by lysosomal cross-correction, a phenomena that allows therapeutic enzymes to be secreted and passed on to other cells. Consequently, not only cells that were transduced by the vector but also surrounding cells receive therapeutic enzyme.
There are also LSDs that are caused by defects in proteins that are bound to a membrane. Since these proteins cannot be secreted, lysosomal cross-correction does not occur and AAV treatments are confined to a smaller number of cells. Therefore, it is more difficult to achieve therapeutic effects. Examples of LSDs deficient in membrane-bound proteins are juvenile Batten disease, Niemann-Pick type C and Sanfilippo type C disease amongst others.
The large number of published pre-clinical animal studies demonstrates the potential of AAV gene therapies. Recent clinical trials show that this treatment is safe and effective for some diseases. One impressive example is the gene therapy trial for spinal muscular atrophy, a fatal childhood motor neuron disease. Following a single intravenous administration of AAV, treated patient lived longer and reached major motor milestones than patient without treatment fail to achieve (Mendell et al. 2017). Despite these encouraging data, it also became clear that gene therapies directly targeted the brain had limited therapeutic effects for other rare neurological disorders, for example LSDs, and more potent AAVs are needed.
Tordo et al. (2018) reported the development of AAV-TT, a novel AAV that was generated by amino acid substitutions in the AAV2 capsid genes. In mice this vector showed a better distribution following localised brain injections (into the caudate putamen) compared with AAV9 and AAV-rh10, which are frequently used vectors for neurodegenerative diseases. Moreover, injections with AAV-TT (into the striatum) in adult mice suffering from Sanfilippo type C lead to a relief of disease-related abnormalities, whereas AAV9 treatment did not have an effect in mutant mice (Tordo et al. 2018).
These findings give hope for the development of more effective gene therapies for CNS diseases including LSDs caused by membrane-bound protein defects. It needs to be pointed out that in this study AAV-TT was not tested in animals larger than rodents and a thorough assessment would be required before clinical use.
Mendell, J. R., et al. (2017). “Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy.” N Engl J Med 377(18): 1713-1722.
Tordo, J., et al. (2018). “A novel adeno-associated virus capsid with enhanced neurotropism corrects a lysosomal transmembrane enzyme deficiency.” Brain 141(7): 2014-2031.