Prof. Don W. Cleveland

Prof. Cleveland

ISP2012 Lecture Course Abstract:

Understanding ALS: from mechanism to therapy

The genes whose mutation is now known to cause the major neurodegenerative diseases are widely or ubiquitously expressed. This is true for each of the genes now known to cause the fatal, adult motor neuron disease Amyotrophic lateral sclerosis (ALS). Unifying features of inherited and sporadic ALS are errors in RNA processing, including cytoplasmic misaccumulation in ALS and frontal temporal dementia (FTD) of TDP-43, an RNA/DNA binding protein and the likely sequestration of one or more RNA binding proteins onto a large hexanucleotide expansion within an intron of the pre-mRNA encoded by the C9orf72 gene. Modeling in mice has demonstrated that one inherited form is caused by mutation in superoxide dismutase (SOD1). Disease mechanism is through an acquired toxicity unrelated to dismutase activity. Toxicity is non-cell autonomous, with mutant SOD1 within motor neurons and oligodendrocytes driving disease onset, while damage within neighboring astrocytes and microglia accelerates disease progression. These findings have validated therapies to slow disease progression, including cell replacement through injection of stem cell derived astrocytic progenitors and infusion of DNA antisense oligonucleotides (ASOs) that direct destruction of SOD1 mRNA widely within the non-human primate nervous system. A final approach is through use of an Adeno-Associated Virus (AAV9) that can cross the blood brain barrier and transduce astroctyes in adult mice. A single peripheral administration of AAV9 encoding an shRNA to SOD1 mRNA slows disease progression, doubling survival after onset.

Prof. Cleveland's ISP2012 Symposium Lecture:
Mechanism and therapy in neurodegenerative disease: ALS and beyond
Prof. Cleveland's ISP2012 Profile
Prof. Cleveland's UCSD Profile:
Profile | Lab

ISP2012 Abstracts