BASE EDITING OF TRANSTHYRETIN GENE

Smart overview of the Invention

Compositions for gene modification are designed to treat conditions caused by the deposition of amyloid fibrils formed from misfolded transthyretin (TTR) proteins. These conditions include hereditary transthyretin amyloidosis leading to polyneuropathy (hATTR-PN) and cardiomyopathy (hATTR-CM), as well as age-related cardiac issues associated with wild-type TTR proteins (ATTRwt). The focus is on utilizing base editing systems to effectively alter the TTR gene.

Polynucleotide Design

An isolated polynucleotide is described, containing a 5′-spacer sequence that is homologous to a targeted protospacer sequence within the TTR gene. This polynucleotide acts as a guide for the base editor system, enabling precise nucleobase alterations. Potential alterations may disrupt critical elements such as start codons or splice sites within the TTR gene, thereby addressing the underlying genetic causes of TTR-related diseases.

Base Editor Fusion Proteins

The application includes compositions that may consist of a nucleic acid encoding a base editor fusion protein. This protein typically includes a programmable DNA binding domain, such as a modified Cas9, and a deaminase enzyme capable of facilitating the desired genetic edits. The design aims to enhance specificity and efficiency in targeting the TTR gene without inducing double-strand breaks in DNA.

Pharmaceutical Applications

Pharmaceutical compositions derived from these gene editing systems are also detailed. These may include lipid nanoparticles (LNPs) that encapsulate the editing components for improved delivery into cells. The LNPs can be formulated to contain cholesterol and other stabilizing agents, ensuring effective administration and uptake in therapeutic applications.

Methods of Administration

Methods for administering these compositions involve delivering the polynucleotide or LNPs to target cells, potentially allowing for one-time treatments that could significantly improve patient outcomes. This approach may provide therapeutic benefits for individuals at risk of or suffering from hereditary transthyretin amyloidosis and related cardiomyopathies, aiming for a long-lasting correction of the genetic defects at play.