Development of gene therapy for early onset Alzheimer’s disease

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Cognitive and memory recovery using genes that block the synthesis of substances causing Alzheimer’s disease

The research team led by Professor Jeong Beom Kim of the Life Science Department at UNIST developed gene therapy to cure Alzheimer’s disease early on. It was confirmed that cognition and memory are restored in the animal model of Alzheimer’s disease through SPON1 gene injection, which blocks the production of amyloid beta, which is a causative agent of Alzheimer’s disease.

Alzheimer’s disease (AD) is a complex, age-related neurodegenerative disease that is the most common form of dementia. However, the cure for AD has not yet been founded. The accumulation of amyloid beta (Aβ) is considered to be a hallmark of AD. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), also known as beta secretase is the initiating enzyme in the amyloidogenic pathway. Blocking BACE1 could reduce the amount of Aβ, but this would also prohibit the other functions of BACE1 in brain physiological activity. SPONDIN1 (SPON1) is known to bind to the BACE1 binding site of the amyloid precursor protein (APP) and blocks the initiating amyloidogenesis. Here, we show the effect of SPON1 in Aβ reduction in vitro in neural cells and in an in vivo AD mouse model. We engineered mouse induced neural stem cells (iNSCs) to express Spon1. iNSCs harboring mouse Spon1 secreted SPON1 protein and reduced the quantity of Aβ when co-cultured with Aβ-secreting Neuro 2a cells. The human SPON1 gene itself also reduced Aβ in HEK 293T cells expressing the human APP transgene with AD-linked mutations through lentiviral-mediated delivery. We also demonstrated that injecting SPON1 reduced the amount of Aβ and ameliorated cognitive dysfunction and memory impairment in 5xFAD mice expressing human APP and PSEN1 transgenes with five AD-linked mutations.

The findings of this study have been published in Cells on May 21, 2020. This has been supported by the Ministry of SMEs and Startups. It was also co-developed with Prof. Kim’s start-up company, Supine therapeutics.

Further reading: Soo Yong Park et al., SPON1 Can Reduce Amyloid Beta and Reverse Cognitive Impairment and Memory Dysfunction in Alzheimer’s Disease Mouse Model, Cells, https://doi.org/10.3390/cells9051275