Streamlining the development of therapeutic genome editing for metabolic diseases Aidan Quigley

Format:

Book

Thesis/Dissertation

Author/Creator:

Quigley, Aidan A., author.

Contributor:

University of Pennsylvania. Cell and Molecular Biology., degree granting institution.

Language:

English

Subjects (All):

Cellular biology.

Pathology.

Biochemistry.

Genetics.

0379.

0487.

0369.

0571.

Local Subjects:

Cellular biology.

Pathology.

Biochemistry.

Genetics.

0379.

0487.

0369.

0571.

Genre:

Academic theses

Physical Description:

1 online resource (98 pages)

Contained In:

Dissertations Abstracts International 87-12B

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2026

Language Note:

English

Summary:

Phenylketonuria (PKU) and argininosuccinic aciduria (ASA, also referred to as argininosuccinate lyase deficiency, ASLD) are inborn errors of metabolism. PKU is caused by pathogenic variants in the phenylalanine hydroxylase (PAH) gene, which encodes the enzyme that converts phenylalanine (Phe) to tyrosine. In PKU patients, this process is disrupted, resulting in the accumulation of blood Phe to neurotoxic levels. In ASA patients, the urea cycle is disrupted, leading to the accumulation of ammonia in the blood. Both diseases result in systemic toxicity. For most PKU patients, elevated Phe levels persist even with chronic dietary and medical treatments. For ASA patients, the only definitive therapy is a highly risky liver transplant.Gene editing offers an alternative to chronic medical treatments or organ transplantation by directly correcting pathogenic variants. A one-time gene editing therapy could deliver potent, durable, and potentially curative outcomes for these patients. In this thesis, we have built upon previously published work from our lab to establish a pipeline for developing gene editing therapies that correct some of the most common pathogenic variants causing PKU and ASA.This pipeline involves the generation of cell lines containing DNA cassettes that span multiple variants of interest. Next, various combinations of base editors and single guide RNAs are screened in these cell lines to identify the most efficacious editing solution for each variant. With a lead editing configuration in hand, a mouse model harboring that pathogenic variant is generated. Simultaneously, we characterize the safety profile of this lead configuration by assessing off-target editing. The editing configuration is then formulated into a delivery vehicle, such as adeno-associated virus (AAV) or lipid nanoparticles (LNPs) and delivered to mice.Using this approach, we identified editing configurations for nine variants of PKU and two variants of ASA. Furthermore, we achieved complete and durable normalization of blood Phe levels with liver corrective editing exceeding 50%. These studies have contributed to the preclinical foundation for an Investigational New Drug (IND) application expected to be filed in 2026

Notes:

Source: Dissertations Abstracts International, Volume: 87-12, Section: B.

Advisors: Musunuru, Kiran Committee members: Powell, Daniel J.; Posey, Avery; Strong, Alanna; Herbst-Nowrouzi, Friederike

Ph.D. University of Pennsylvania 2026

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798247981206

Access Restriction:

Restricted for use by site license