Metabolic diseases are generally severe genetic diseases without good treatment options. While individual metabolic diseases are rare, as a group, they affect many patients an represent one of the major causes of childhood death in Europe. Methylmalonic acidemia (MMA) is an example of such a rare genetic metabolic disorder. MMA affects the body’s ability to break down specific amino acids. Even when strictly adhering to current therapeutic strategies, patients may still develop metabolic decompensations, neurologic symptoms, kidney failure, and acute blindness. Liver transplantation can prevent further accumulation of toxic metabolites, but is a high-risk operation for MMA patients and requires lifelong immune suppression. Correction of the genetic cause of disease would revolutionize outcomes for these patients, especially how that MMA is increasingly detected in neonatal screening programs, which allows identification of patients prior to the onset of irreversible damage. However, efficiency, safety, versatility and delivery of precise gene editing is currently insufficient for clinical gene-correction therapies.
The aim of this proposal is to develop an in vivo gene-editing therapy program targeting the liver for patients with metabolic disease. As a proof-of-principle, we will repair genetic causes of MMA, validate this in personalized cell and mouse models, and lay the groundwork for human trials.
To this end, I will:
(1) Generate a clinically applicable gene-editing system. We will employ prime editing, a novel gene-editing technique, we recently demonstrated to accurately correct different mutations in patient-derived cell models. Using an innovative reporter and patient-derived cell models, I will develop prime editing into an efficient and safe strategy to correct >90% of patient mutations.
(2) Create a delivery system for the large prime-editing machinery with mRNA-packed lipid nanoparticles to target the liver.
(3) Develop a roadmap for tailored gene-correction therapies for a common human MMA mutation.
This foundational work will lay the basis for broad clinical application of precise gene-editing therapies.
