US20260242796
2026-08-20
Chemistry; metallurgy
C12N15/1137
The patent application describes oligonucleotides designed to enhance the expression of glucocerebrosidase (GBA) in cells. These oligonucleotides are particularly useful in addressing diseases such as Gaucher's disease and Parkinson's disease, which are linked to reduced GBA expression. The oligonucleotides work by targeting complementary sequences in the 3′ untranslated region (UTR) of the GBA mRNA transcript, potentially offering a therapeutic approach that differs from existing treatments like enzyme replacement therapy (ERT) and substrate reduction therapy (SRT).
The invention focuses on the development and application of antisense oligonucleotides that can upregulate GBA expression. These oligonucleotides may be used in various forms, including conjugates and salts, and are formulated into pharmaceutical compositions. The goal is to provide a novel treatment method for disorders associated with low GBA activity, such as Gaucher's and Parkinson's diseases, by directly influencing the genetic expression mechanisms at the mRNA level.
GBA is a lysosomal enzyme crucial for breaking down glucocerebroside, a component of cell membranes. Mutations in the GBA gene can lead to Gaucher's disease, characterized by symptoms like fatigue and organ enlargement, and have been associated with Parkinson's disease. Current treatments, like ERT, are limited by their inability to cross the blood-brain barrier and potential immune responses. Therefore, new treatments that can effectively increase GBA expression are needed to address these limitations.
The antisense oligonucleotides described are designed to bind to specific sequences within the 3′ UTR of the GBA mRNA, thereby enhancing its expression. These oligonucleotides range from 8 to 40 nucleotides in length and can inhibit the binding of microRNAs, such as miR-22-3p, that downregulate GBA expression. The oligonucleotides may incorporate various modifications, including 2′-O-methyl RNA and locked nucleic acid (LNA) nucleosides, to enhance stability and efficacy.
The invention provides a promising alternative to existing therapies for Gaucher's and Parkinson's diseases. By increasing GBA expression at the genetic level, these oligonucleotides could potentially overcome the drawbacks of ERT and SRT, such as immune responses and limited efficacy in neuronopathic conditions. This approach could lead to more effective management of these diseases, reducing the need for lifelong treatment and improving patient outcomes.