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In Vivo Gene Therapy Candidate for Metachromatic Leukodystrophy in Development

Preclinical data showed hARSA activity levels in the brain that are predictive of functional improvements.

Homology Medicines has announced details regarding HMI-204, an in vivo, single-dose gene therapy candidate intended for the treatment of metachromatic leukodystrophy (MLD) that is currently under development.1

Preclinical data from a murine model of MLD showed that a single intravenous (IV) dose of HMI-204 led to increased expression of human arylsulfatase A (hARSA) protein, the disease-targeted enzyme, in multiple brain regions and cell types, as well as hARSA activity levels in the brain that are predictive of functional improvements. Increased hARSA activity in the serum was also observed.

HMI-204 is an optimized version of Homology Medicine’s earlier MLD gene therapy candidate, HMI-202, which was originally selected for further development in late 2018 following promising early data presented at the Society for Neuroscience annual meeting.2

“Efforts to enhance our original MLD candidate led to our optimized candidate, which has a better therapeutic profile with respect to expression and packaging, while retaining its key differentiator of addressing the central nervous system (CNS) and peripheral organ manifestations of the disease with a single IV administration,” Albert Seymour, PhD, president and chief scientific officer of Homology Medicines, said in a statement.1 “In addition to our understanding of MLD disease biology and our team’s prior experience in developing potential treatments for this disorder, we were able to apply our expertise in vector design and manufacturing to optimize our candidate. We believe that the preclinical data demonstrate its potential to make a meaningful difference for patients whose current treatment options are limited to ex vivo approaches that include difficult pre-conditioning regimens. We look forward to sharing data from this development candidate at future meetings.”

Activity levels of hARSA in the 2018 preclinical data from several human-derived adeno-associated virus vector (AAVHSC) candidates reached 30% to 115% of normal activity levels in one candidate, already deemed well above the therapeutic target of 10% to 15%.3 Homology Medicines indicated that the expression levels now seen in the clinical data from HMI-204 are substantially above the minimum necessary to correct the MLD disease phenotype.1 Additionally, HMI-204 was able to successfully cross the blood-brain barrier, in-and-of-itself considered one of the major challenges of developing single-dose gene therapies targeting neurological disorders.1,3

“We are pleased to report that our vectors effectively reach the central and peripheral nervous system following systemic administration,” Seymour said in a statement regarding the candidates in 2018.3 “We are striving to provide a one-time treatment option that may lead to a cure for patients...”

Homology Medicines said that it is actively seeking a partner to help advance the development of HMI-204.1 In addition to its MLD program, the company is also developing HMI-203, a gene therapy for the treatment of Hunter syndrome, and HMI-102, a gene therapy for the treatment of phenylketonuria. HMI-102 is being investigated in a phase 1/2 clinical trial which was recently released from a clinical hold in June of this year.

1. Homology Medicines announces optimized, in vivo gene therapy candidate for the treatment of metachromatic leukodystrophy. News release. Homology Medicines, Inc. August 11, 2022. https://www.homologymedicines.com/news-story/homology-medicines-announces-optimized-in-vivo-gene-therapy-candidate-for-the-treatment-of-metachromatic-leukodystrophy 
2. Homology Medicines achieves 2018 goals and prepares PKU gene therapy program for the clinic with initial data expected in 2019. News release. Homology Medicines, Inc. January 7, 2019. https://www.homologymedicines.com/news-story/homology-medicines-achieves-2018-goals-and-prepares-pku-gene-therapy-progra 
3. Homology Medicines presents data on platform’s ability to target the central and peripheral nervous system and therapeutic potential in the rare disease metachromatic leukodystrophy. News release. Homology Medicines, Inc. November 7, 2019. https://www.homologymedicines.com/news-story/homology-medicines-presents-data-on-platforms-ability-to-target-the-central