Developing an antisense therapy approach for Kennedy’s disease

Spinal bulbar muscular atrophy (SBMA), commonly known as Kennedy's disease (KD), is an X-linked motor neuron disease affecting males. 


This project will use next-generation DNA designer drugs called antisense oligonucleotides (ASOs) to target and suppress expression of mutant AR linked to KD. 

KD is caused by pathogenic CAG trinucleotide repeat expansion in exon 1 of the androgen receptor (AR) gene, leading to progressive loss of lower motor neurons and muscle weakness and wasting.  AR binds and mediates the biological effects of androgens such as testosterone, explaining the male preponderence of KD.  KD-linked mutations in AR are proposed to cause a toxic gain-of-function, resulting in accumulation of nuclear inclusions of AR protein that damage motor neurons.  Gene and molecular therapies that suppress levels of mutant AR are therefore a rationale approach to effective treatment of KD.

ASOs will be designed and screened for AR knockdown activity using mouse neuronal cell lines expressing GFP-tagged AR constructs and KD patient induced pluripotent stem cell (iSPC)-derived motor neurons.  The most effective ASO will advance to treatment of a transgenic mouse model of KD to determine effects on symptoms, neuropathology and AR protein aggregation.  The outcome of this project will be an ASO therapeutic candidate for KD.

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