Gene therapy for the rare inherited disease phenylketonuria (PKU)

July 15, 2021

USF Health Genetics and Metabolism and Tampa General Hospital (TGH) have teamed up to deliver investigational gene therapies for the rare inherited disease phenylketonuria (PKU) as part of a pivotal multisite clinical trial.

USF Health is one of four sites – three in the U.S. and one in the United Kingdom – currently participating in a phase 1/2, open-label clinical trial testing the safety and effectiveness of an adenovirus vector-mediated gene therapy for PKU. The study expects to enroll up to 100 patients ages 15 and older. Many PKU patients struggle to stick to a strict low-protein diet needed to control harmful levels of the amino acid phenylalanine (Phe), which is not metabolized in people with PKU.

The first patient intravenously administered the investigational gene therapy (called BMN 307) at Tampa General in early May was the second PKU patient in the U.S. to receive the treatment as part of the multicenter trial, Dr. Sanchez-Valle said. The USF Health Metabolic Genetics Clinic has identified several more potentially eligible patients for this trial.

Babies born with PKU have defects in a metabolic gene that makes the enzyme phenylalanine hydroxylase (PAH). This PAH enzyme is needed to break down Phe, an amino acid in all protein-containing foods, including chicken, meat, eggs, dairy, nuts, grains, and legumes. Left untreated, high or unstable levels of Phe become toxic to the brain and may lead to serious neurological and neuropsychological complications, affecting the way a person thinks, feels, and acts. The lifelong condition is controlled primarily by eating a very restrictive, low-protein diet that is difficult to maintain.

Two drugs are approved in the U.S. to help treat PKU. Kuvan, a PAH enzyme activator, gives a small percentage of patients slightly more flexibility in their diet. The injectable enzyme substitution Palynziq, available for adults only, is the first allowing patients to eat a normal diet. However, the drug carries a warning about the possibility of severe immune reactions, and some patients are averse to giving themselves daily injections and risking side effects.

The gene therapy uses an adeno-associated viral vector (virus engineered to be harmless) to shuttle a fully functional copy of the PAH enzyme gene into the liver cells where Phe is broken down. Once the vector infects the liver cells, the cells read the code from the normal gene and begin naturally reproducing the missing or deficient PAH enzyme.

Advances in technology have opened new ways of delivering targeted gene therapies, including creating other vectors to deliver therapeutic genes, like lentiviruses and lipid nanoparticles, as well as possibly fixing PAH mutations with gene editing tools such as CRISPR.

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