Silencing of Amyloid Precursor Protein Expression Using a New Engineered Delta Ribozyme

Abstract

<jats:p>Alzheimer's disease (AD) etiological studies suggest that an elevation in amyloid-β peptides (Aβ) level contributes to aggregations of the peptide and subsequent development of the disease. The major constituent of these amyloid peptides is the 1 to 40–42 residue peptide (Aβ<jats:sub>40−42</jats:sub>) derived from amyloid protein precursor (APP). Most likely, reducing Aβ levels in the brain may block both its aggregation and neurotoxicity and would be beneficial for patients with AD. Among the several possible ways to lower Aβ accumulation in the cells, we have selectively chosen to target the primary step in the Aβ cascade, namely, to reduce APP gene expression. Toward this end, we engineered specific SOFA-HDV ribozymes, a new generation of catalytic RNA tools, to decrease APP mRNA levels. Additionally, we demonstrated that APP-ribozymes are effective at decreasing APP mRNA and protein levels as well as Aβ levels in neuronal cells. Our results could lay the groundwork for a new protective treatment for AD.</jats:p>

Gene suppression approaches to neurodegeneration

“…AAV delivery of a ribozyme against alpha-synuclein into the substantia nigra of a rat model of PD reduced alpha-synuclein protein levels and neuronal loss [ 39 ]. Finally, a new generation of ribozymes (hepatitis delta virus (HDV)) has been used in neuroblastoma cells to reduce the expression of amyloid precursor protein (APP) by 70% and the total secretion of amyloid-beta peptides by 30%, thus raising the possibility of ribozymes as therapeutics in AD [ 40 ].…”

Delivering a disease-modifying treatment for Huntington's disease

“…AAV delivery of a ribozyme against a-synuclein, into the substantia nigra, reduced a-synuclein protein levels and improved cell survival of tyrosine hydroxylase-positive neurons [17]. Moreover, hepatitis delta virus (HDV) ribozymes, a new generation of ribozymes, have been successfully used in SH-SY5Y neuroblastoma cell cultures to reduce the expression of amyloid protein precursor (APP) by up to 70%, and the total secretion level of amyloid-b peptides by 30% [18]. Therefore, these HDV ribozymes are been considered as potential therapeutics for Alzheimer's disease (AD), but require further investigation in animal models.…”