By Albert Seymour, Ph.D., President and CEO, Homology Medicines, Inc.

At Homology, we have a lofty goal, which is to deliver to patients one-time, in vivo (in the body) treatments for genetic disorders. We believe this mission is possible because of the powerful platform that underlies our pipeline of development candidates. Although discovered just shy of ten years ago, our AAVHSC platform already underlies the first gene editing clinical trial for phenylketonuria (PKU) and the first systemic gene therapy clinical trial for Hunter syndrome, also known as mucopolysaccharidosis II (MPS II).

We deploy our AAVHSC platform in three distinct ways based on the disease we are targeting:

• Gene editing that leverages the highly precise natural DNA repair process of homologous recombination;
• Gene therapy that takes advantage of the tissue distribution of our platform; and
• GTx-mAb, or gene therapy to create monoclonal antibodies.

Pairing our AAVHSCs to Selected Indications

AAVHSCs are naturally occurring adeno-associated viruses (AAVs) that were discovered in human hematopoietic stem cells (HSCs) in 2014 (Smith, 2014). When used therapeutically, the AAVs do not cause disease, but instead efficiently carry genetic material to tissues and organs inside the body. When delivered intravenously (I.V.), AAVHSCs can enter, or transduce, cells of multiple organs and cross the blood-brain barrier and blood-nerve-barrier, reaching critical cells in the central nervous system (CNS), including the brain (Ellsworth, 2019).

What is particularly interesting about AAVHSCs, is that they all map to Clade F (same viral family) but the genetic differences they have lead to different biodistribution profiles. For example, AAVHSC15 transduces the liver, CNS, heart, lungs, skeletal muscle and kidneys; whereas AAVHSC16 broadly targets the CNS and peripheral nervous system, along with the heart and skeletal muscle, but only minimally targets the liver (Smith, 2022).

Having a family of 15 AAVHSCs means that we can select the appropriate AAVHSC as a delivery vehicle for treating a particular disease by matching its biodistribution profile to the tissue or tissue types we want to treat in that disease. Taking it further, our family of AAVHSCs can also be designed in the ways described above that is most appropriate for the disease being targeted – through nuclease-free gene editing, gene therapy or the GTx-mAb modality.

AAVHSCs for Genetic Medicines

Across our entire platform, all of our AAVHSC-based development candidates are designed to be delivered as a single component (i.e., one vector). This reduces complexity in delivery, biology and manufacturing. Additionally, all are designed as one-time genetic medicines, which can be delivered through an I.V. infusion.

For gene editing, our AAVHSC vectors are designed with long stretches of DNA, or homology arms, which guide a gene to the exact location in the genome where it is needed to integrate. Our vectors enable homologous recombination to insert a corrective gene sequence without detectable on-target or off-target errors (Huei-Mei Chen, 2020 ). Gene editing is needed in growing organs that have active cellular division, like a child’s liver. For example, HMI-103 is our one-time gene editing clinical candidate for people with PKU, which is currently in a Phase 1 clinical trial. PKU is caused by mutations in the PAH gene, which disrupt the normal metabolism of phenylalanine, which comes into the body through dietary protein. HMI-103 is designed to harness the body’s natural DNA repair process of homologous recombination to insert a functional gene and liver-specific promoter, and to maximize PAH levels with episomal expression in all transduced liver cells. Since PKU is a liver-based disease, in order to provide a one-time treatment to a pediatric patient, a gene editing approach is warranted so that the corrective gene sequence will be passed on during cell division. HMI-103 and the pheEDIT trial will be the subject of an upcoming article, but you can learn more here: https://clinicaltrials.gov/ct2/show/NCT05222178.

Our gene therapy candidates utilize our AAVHSC vectors to deliver a functional gene and promoter to a cell where there is a missing or non-functional gene. Hunter syndrome is a rare, X-linked lysosomal storage disorder caused by mutations in the iduronate-2-sulfatase (IDS) gene. IDS is responsible for producing the I2S enzyme that breaks down large sugar molecules, or cellular waste, called glycosaminoglycans (GAGs). HMI-203, our one-time gene therapy clinical candidate for adults with Hunter syndrome is currently in a Phase 1 clinical trial in the U.S. and Canada. HMI-203, uses an AAVHSC to deliver functional copies of the IDS gene throughout the body, including to peripheral organs and the CNS. Learn more about the juMPStart trial here: https://clinicaltrials.gov/ct2/show/NCT05238324

GTx-mAb represents the third arm of Homology’s platform and is designed to deliver one-time in vivo gene therapies to produce antibodies from the liver and secrete them throughout the body. This approach has advantages over periodic I.V. infusions of a therapeutic antibody, where patients may experience “peaks” in the therapeutic effects of the antibody shortly after infusion and “troughs” shortly before the next infusion. HMI-104 is our GTx-mAb development candidate for paroxysmal nocturnal hemoglobinuria (PNH). We have the potential to expand HMI-104 into additional complement-mediated indications and apply GTx-mAb to other targets and larger therapeutic indications.

In future articles, we will examine each arm of our platform and dig into our development candidates. Our team is expanding the possibility of one-time treatments for genetic disorders, and we are excited to share that with you.