Spinal Muscular Atrophy (SMA)
The autosomal recessive motor neuron disease proximal SMA is the most common inherited cause of infant mortality world wide. Motor neuron degeneration causes profound skeletal muscle weakness of proximal limb, trunk, and respiratory muscles. SMA is caused by recessive mutations of the survival motor neuron 1 (SMN1) gene, retention of the SMN2 gene in variable copy number, and deficiency of SMN protein. Disease severity in patients correlates inversely with SMN2 copy number and SMN expression. The SMN protein plays an essential role in synthesizing small nuclear ribonuclear proteins (snRNPs), which are critical components of the spliceosome, but how deficiency of this ubiquitously expressed protein causes specific vulnerability of motor neurons remains unknown.
Defining mechanisms regulating SMN expression
SMA is caused by deficient expression levels of SMN protein, thus understanding the mechanisms that regulate SMN transcription and translation are central to developing and optimizing treatments. We have demonstrated that SMN levels decline during development (Ramos, JCI 2019) and have characterized epigentic mechanisms that may regulate transcription during neuronal differentiation including histone acetylation and long noncoding RNAs (lncRNAs) (d'Ydewalle, Neuron 2017). We are also studying mechanisms regulating SMN mRNA metabolism including stability, trafficking, and pre-mRNA splicing.
Investigating the molecular and cellular mechanisms of SMA
In order to understand how SMN protein deficiency causes motor neuron dysfunction and degeneration, we study molecular, cellular, and physiological disease pathomechanisms. Over the last decade, we have defined abnormalities of both neuromuscular junction and central motor synapse elaboration and function as well as impairments of myofiber growth. Our most recent studies in human patients and SMA mouse models identify a striking impairment of motor axon radial growth and Schwann sorting that begins in utero and is followed by rapid degeneration of the most immature axons postnatally (Kong et al, Science Transl Med, 2020). These findings have immediate implications for efforts to minimize treatment delays of patients. Additionally, understanding the molecular mechanisms
underlying developmental delays as well
as degenerative events could lead to novel
therapeutics. We are currently defining
these mechanisms by integrating unbiased
'omicsstudies with deep phenotyping
studies of human tissues collected during
expedited autopsies, morphological and
genetic studies in mouse models using
approaches such as electron microscopy
and iDISCO (allowing visualization of the entire nervous system in 3D after tissue clearing), and structural and physiological studies of iPSC derived motor neurons cultured in novel compartmentalized chambers.
Therapeutic development for SMA
Remarkable success in therapeutics development for SMA has led to 3 SMN-inducing treatments for SMA patients including a splice switching antisense oligonucleotide, a splice switching small molecule and AAV9 mediated gene replacement therapy (Sumner, Crawford JCI 2018). These advances represent a breakthrough and lessons learned will be applicable to many neurogenetic disorders. However, therapeutic efficacy remains variable in patients. We aim to further understand the factors that underlie this variability in order to optimize current therapeutics and develop combinatorial treatment strategies. We are currently exploring the feasibility of in utero treatment for the most severely affected patients. We are also developing novel biomarkers for SMA including blood neurofilament levels.