Homology Medicines’ candidate treatments in gene editing and gene therapy significantly reduced phenylalanine levels — which are dangerously high in people with phenylketonuria (PKU) — in a mouse model of the disease, the company announced.
A clinical study of a gene editing therapy, HMI-102, in adults with PKU is also underway.
The preclinical data were given in oral and poster presentations at the European Society of Gene & Cell Therapy (ESGCT) 27th Annual Congress, which took place Oct. 22-25 in Barcelona.
PKU is characterized by the toxic build-up of phenylalanine — an amino acid (the building blocks of proteins) obtained through the diet — in the blood and organs. Since brain nerve cells are particularly sensitive to phenylalanine, excessive amounts of this amino acid can lead to brain damage.
PKU is linked to more than 500 mutations in the PAH gene, which has the instructions to produce phenylalanine hydroxylase (PAH), an enzyme responsible for the conversion of phenylalanine into another amino acid, tyrosine.
PAH mutations lower the levels of PAH activity, preventing it from effectively processing phenylalanine and leading to mild, moderate, or severe PKU, depending on the enzyme’s activity levels.
Currently approved PKU treatments — Kuvan (sapropterin dihydrochloride) and Palynziq (pegvaliase-pqpz) by BioMarin Pharmaceutical — help to control phenylalanine levels by boosting PAH activity or PAH-independent phenylalanine breakdown.
Homology Medicines is working on two different genetic approaches to increase the production of PAH protein as a potential therapy for PKU patients. Both approaches use the company’s harmless version of the adeno-associated virus (AAV) originally derived from human blood stem cells — called AAVHSC — to deliver the functional PAH gene precisely and effectively into liver cells.
The liver is a frequent target in gene therapy, as it plays a central role in metabolism and the production of blood proteins.
AAVHSCs enter the cell’s nucleus, and can be designed to introduce (gene editing) or not (gene therapy) the functional PAH gene into the cell’s DNA (genome).
Homology’s HMI-103 gene editing candidate for children with PKU has the potential to correct the defective PAH gene in the genome by replacing it with a functional copy through a natural DNA repair process called homologous recombination (known as nuclease-free gene editing).
This approach is thought to be highly specific and safer (by avoiding off-target effects) than commonly used gene therapy approaches, as it does not rely on error-prone nucleases — enzymes that make small cuts in the DNA to promote the introduction of genes into the genome through a different mechanism of DNA repair, Homology reports.
The company’s HMI-102 gene therapy candidate for adults with PKU is designed to deliver a functional copy of the PAH gene and a specific DNA sequence into cells to induce the production of PAH protein without any integration into the genome.
HMI-102’s safety and effectiveness in reducing blood levels of phenylalanine in PKU patients is now being studied in the open-label, randomized Phase 1/2 pheNIX clinical trial (NCT03952156). pheNIX is the first gene therapy clinical trial in PKU, and is now enrolling up to 21 adults, ages 18 to 55, at four sites in the U.S.
Preclinical results from the HMI-103 gene editing candidate showed that a single administration of HMI-103’s mouse version led to a sustained reduction in phenylalanine levels to therapeutic levels in a PKU mouse model, Homology reported in a press release.
HMI-103 also selectively targeted and edited human liver cells in a mouse model with a mix of human and mouse liver cells, showing that it acts in a species-specific way. No unwanted additional genetic changes at the site of gene editing were detected, supporting HMI-103’s specificity and safety. HMI-103 was previously shown to also increase the production of PAH protein in this model.
The company also presented data on the effectiveness of HMI-102’s mouse version with different amounts of empty viruses — a normal by-product of virus manufacturing, whose impact on gene therapy effectiveness is still debated — in a PKU mouse model.
Results showed that a wide range of empty virus ratios resulted in comparable levels of HMI-102 biological activity and a significant and sustained reduction of phenylalanine levels.
“These data suggest that AAVHSCs may be less sensitive to empty [viruses], which is an important aspect for manufacturing,” Tim Kelly, Homology’s chief technical operations officer, said in the release.
AAVHSC was also found to be more effective in introducing the functional PAH gene into cells and leading to normal levels of phenylalanine in PKU mice than AAV5, another virus of the AAV family commonly used in gene therapies.
“AAVHSCs reduced the levels of [phenylalanine] to within the normal range regardless of full to empty [virus] ratios, and showed improved therapeutic activity in a PKU model compared to AAV5,” Kelly said.
HMI-102 has been granted orphan drug designation in the U.S. and European Union, and more recently, fast track designation by the U.S. Food and Drug Administration (FDA) for the treatment of PKU. These designations are expected to facilitate HMI-102’s development and review process.