Download Cleveland Synopsis of Contributions to Science and Medicine (May

May 12, 2017
CURRICULUM VITAE
Don W. Cleveland, Ph.D.
SYNOPSIS OF D.W. CLEVELAND’S CONTRIBUTIONS TO SCIENCE
Cleveland has made ground-breaking contributions in the regulation of assembly of
mitotic spindles and chromosome movement. He discovered the microtubule associated
protein tau (mutation in which causes human cognitive disease), the tubulin gene
families encoding the major subunits of microtubules, and the first mammalian example
of control of gene expression through regulated RNA instability. He identified
components required for microtubule nucleation and anchoring during spindle assembly.
He discovered CENP-E, the centromere-associated, microtubule-motor that he showed to
be a microtubule “tip tracker” essential for powering congression of initially misaligned
chromosomes, chromosome attachment at centromeres, and maintenance of
chromosome congression. Using all purified components, he identified that unattached
centromeres/kinetochores initiate a two step catalytic cascade signaling mechanism that
represents the mitotic checkpoint, the cell cycle control mechanism that prevents errors
of chromosome segregation in mitosis. He identified that the meiotic counterpart of the
mitotic checkpoint is silenced without development of interkinetochore tension, thereby
uncovering a mechanistic basis for the high error frequency of female meiosis in
mammals.
The centromere is the basic determinant of chromosome inheritance. Unlike genes
carried on those chromosomes, however, centromere position is defined by an epigenetic
mark, not by DNA sequence. Cleveland identified the basis for epigenetic inheritance of
centromere identity. He demonstrated it to be chromatin assembled with the histone H3
variant CENP-A, which he showed to be able to template its own replication through
action HJURP, the histone chaperone/chromatin loader he and his team discovered.
In neuro cell biology, other major contributions emerged from Cleveland’s demonstration
that extreme asymmetry of neurons is achieved with a deformable array of interlinked
neurofilaments, microtubules and actin. He showed that disorganization of
neurofilaments causes selective failure of motor neurons in mice and humans. He then
demonstrated that similar disease could also arise by a toxicity of mutant superoxide
dismutase unrelated to its normal activity, thereby uncovering the mechanism underlying
a major genetic form of Amyotrophic Lateral Sclerosis (ALS). He also showed that motor
neuron death in inherited ALS is non-cell autonomous, requiring mutant damage to both
motor neurons and the neighboring supporting cells. This discovery has wide implications
for other major neurodegenerative diseases, since the inherited forms of each are also
caused by widely expressed mutant genes. Cleveland’s findings demonstrated the
attractiveness of stem cell replacement of non-neuronal cells as a viable therapy in ALS.
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May 12, 2017
CURRICULUM VITAE
Don W. Cleveland, Ph.D.
SYNOPSIS OF D.W. CLEVELAND’S CONTRIBUTIONS TO MEDICINE
Cleveland has made field leading discoveries into the causes and treatment of ALS and
Huntington’s diseases, with implications for a set of additional neurodegenerative/
neuromuscular diseases that include spinal muscular atrophy, myotonic dystrophy and
Alzheimer’s and chronic traumatic brain injury. His efforts identified key steps that
trigger disease and that accelerate ALS disease progression from mutation in superoxide
dismutase. These findings have redirected efforts at stem cell and gene silencing
therapies in ALS. Cleveland also identified tau, the microtubule associated protein which
misaccumulates in intraneuronal tangles in essentially all instances of Alzheimer’s
disease and whose misfolding mediates a slow cell-to-cell spread that is causative of the
chronic traumatic encephalopathy associated with repeated brain injury now recognized
to be prominent in athletics.
Cleveland developed a pair of gene silencing therapies widely applicable in human
neurodegenerative disease. His initial approach established utility of “designer DNA
drugs” (short single stranded DNAs) that mediate catalytic, RNase H-dependent
degradation of the RNA encoded by any selected gene. He demonstrated that single dose
infusion of such designer DNA drugs produces durable efficacy (lasting more than three
months) throughout the entirety of the rodent and non-human nervous systems. An initial
application was for an inherited form of ALS and which entered clinical trial in 2010. In
2013, an extension of this approach entered clinical trial for myotonic dystrophy.
Additional trials initiated for Huntington’s disease in 2015 and ALS in 2016, and one is
anticipated to initiate early in 2017 for the most frequent cause of ALS and Frontal
Temporal Degeneration (FTD), hexanucleotide expansion in the C9orf72 gene.
Extensions for development of clinical trials for silencing genes central to Alzheimer’s
and Parkinson’s diseases, chronic brain injury, and a set of ataxias are ongoing. An
additional application is in trial with a designer DNA drug chemically modified so that it
is not recognized by RNase H (and therefore does not stimulate RNA degradation) but
acts to correct an RNA splicing abnormality in spinal muscular atrophy, one of the most
abundant genetic diseases of children.
Cleveland has pioneered additional gene silencing or gene replacement therapies for
human nervous system disease using adenoassociated virus (AAV). He and his colleagues
have shown remarkably broad delivery within the nervous system and they are now
developing this for human clinical trial expected to initiate in 2017 using AAV encoding a
short hairpin RNA which acts with the RNA-induced silencing complex (RISC) to trigger
degradation of the RNA encoded by a mutated superoxide dismutase gene causative of
inherited ALS.
Lastly, with his corporate partner Ionis Pharmaceuticals, Cleveland developed the first
synthetic CRISPR RNA, demonstrating that it can direct and activate transient, DNA site
sequence-specific Cas9 nuclease activity which will cleave and inactivate a target gene.
This approach is now in development for therapy combining AAV gene delivery and
synthetic CRISPR infusion for gene silencing or correction.
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May 12, 2017
CURRICULUM VITAE
Don W. Cleveland, Ph.D.
Aneuploidy - acquisition of a chromosome content other than a multiple of the haploid
number – has long been known to be a frequent component of tumorigenesis. By
generating mice that develop aneuploidy at high rates, Cleveland tested the 100 year old
hypothesis that aneuploidy drives tumorigenesis. He demonstrated that aneuploidy drives
tumorigenesis in some genetic contexts, but suppresses it when combined with
tumorigenic mechanisms that independently generate high levels of aneuploidy.
Cleveland also discovered the centromere motor CENP-E. His demonstration that
inhibition of it induces chronic mitotic arrest followed by cell death for a variety of
tumor cells, has enabled development of inhibitors of the CENP-E motor. GlaxoSmithKline
and Cytokinetics have taken CENP-E inhibitors to clinical trial for human solid tumors.
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