Shape Therapeutics, Inc. is pioneering a novel approach in genetic medicine by focusing on the transient instructions within the cell rather than the permanent genetic blueprint. The company develops programmable RNA medicines that aim to correct genetic errors and modulate protein function at the messenger RNA (mRNA) level. This focus on ribonucleic acid (RNA) offers a distinct therapeutic modality compared to traditional methods of altering the genome itself.
Defining RNA Editing
RNA editing is a mechanism that allows for the precise alteration of genetic instructions after they have been transcribed from DNA. Unlike DNA, the permanent archival copy, RNA molecules like messenger RNA (mRNA) are transient intermediaries that carry instructions for building proteins. This technology specifically targets the mRNA to correct a faulty instruction before it reaches the cell’s protein-making machinery.
The core of this process involves Adenosine-to-Inosine (A-to-I) editing. Adenosine (A) is converted into Inosine (I), which is the therapeutic action. Since cellular machinery recognizes Inosine as Guanosine (G), this single-letter change effectively corrects a pathogenic A-to-G mutation or introduces a beneficial amino acid change. The transient nature of mRNA means these edits are not permanent additions to the genome, allowing for a tunable and reversible therapeutic effect.
The Mechanism of RNA Modification
Shape Therapeutics’ proprietary technology, termed RNAfix, leverages a naturally occurring human enzyme to execute this precise modification. The therapy uses the endogenous enzyme Adenosine Deaminase Acting on RNA (ADAR), which is already present in human cells. ADAR’s natural function is to convert adenosine to inosine within double-stranded RNA structures.
The therapeutic strategy involves introducing a proprietary guide RNA (gRNA) into the cell, often delivered via an Adeno-Associated Virus (AAV) vector. This engineered gRNA is designed to be complementary to the target mRNA sequence that requires editing. When the gRNA binds to the target mRNA, it forms a specific double-stranded RNA structure that the ADAR enzyme recognizes.
This binding recruits the ADAR enzyme to the precise location on the mRNA, directing the A-to-I conversion only at the intended site. Shape Therapeutics employs artificial intelligence models, such as DeepREAD, trained on millions of experimental data points to engineer gRNA sequences. This computational approach ensures high editing efficiency and specificity, successfully utilizing the body’s natural editing machinery to correct a specific genetic error.
Advantages Over DNA Gene Editing
The strategy of editing RNA offers several distinct advantages compared to methods that permanently alter genomic DNA, such as CRISPR/Cas9. A primary benefit is the avoidance of permanent changes to the cell’s master blueprint. Since the edit only affects the mRNA transcripts, which are constantly being degraded and replaced, the therapeutic effect is temporary and can be tuned or stopped if necessary.
This transient nature contributes to an improved safety profile. DNA editing systems risk introducing unintended genomic alterations, known as off-target mutations, or causing permanent double-strand breaks in the DNA. RNA editing minimizes the risk of these irreversible changes because it operates on the temporary RNA copy, not the permanent DNA genome.
Furthermore, RNA editing allows for the precise correction of point mutations without disturbing the surrounding DNA sequence. The use of the body’s own ADAR enzyme also means the therapy does not require the introduction of bulky, foreign bacterial proteins, which can sometimes trigger an unwanted immune response.
Targeted Disease Areas and Pipeline
The programmable nature of the RNA editing platform enables its application across a wide spectrum of disorders with a known genetic origin. Shape Therapeutics is prioritizing the development of therapies for inherited genetic disorders, particularly those affecting the central nervous system and the eye. The internal pipeline includes neurological diseases like Rett syndrome, a severe neurodevelopmental disorder, and Parkinson’s disease.
The company is also targeting specific ocular conditions, such as ABCA4-related diseases, which cause progressive vision loss. Beyond single-gene disorders, the technology holds promise for broader applications requiring transient modulation of protein function, such as in inflammatory conditions or infectious disease. The platform is also being explored in corporate collaborations, including a partnership with a global pharmaceutical company for undisclosed targets in neurological and other rare diseases.