RARE Daily

Avrobio Expands Gene Therapy Pipeline with Program for Hunter Syndrome

October 5, 2020

Rare Daily Staff

Avrobio entered into an exclusive, worldwide license agreement and a collaborative research funding agreement with The University of Manchester for an experimental lentiviral gene therapy for mucopolysaccharidosis type II, or Hunter syndrome, a rare and deadly lysosomal disorder that primarily affects young boys.

Under their agreement, Avrobio will pay The University of Manchester an upfront cash payment and additional payments based on development and regulatory milestones. The company will also pay The University of Manchester a mid-single digit percentage royalty on annual net sales of licensed products. Avrobio will cover budgeted phase 1/2 clinical trial costs.

The deal adds a fifth experimental lentiviral gene therapy pipeline targeting lysosomal disorders to Avrobio’s pipeline, which includes programs for Fabry, Gaucher and Pompe diseases.

Hunter syndrome, also known as MPS II, is a genetic metabolic condition that affects one in 100,000 to one in 170,000 individuals. Individuals affected with a severe form of the condition begin to lose basic functional skills between the ages of two and four and have a shortened life expectancy.

The condition is caused by a deficiency of the iduronate 2-sulfatase (IDS) enzyme, which is essential for breaking down large sugar molecules called glycosaminoglycans (GAGs, also known as mucopolysaccharides). Without functional IDS, toxic levels of GAGs build up throughout the body and central nervous system, causing a wide range of symptoms including cognitive decline and cardiac and respiratory dysfunction. Approximately two-thirds of patients with Hunter Syndrome suffer from progressive cognitive impairment in addition to other severe clinical manifestations. Standard enzyme replacement therapy does not result in sufficient brain concentrations to adequately address cognitive impairment.

The experimental therapy targeting Hunter syndrome involves ex vivo transduction of the patient’s own hematopoietic stem cells with a therapeutic transgene designed to express functional enzyme the patient needs to maintain cellular health, coupled to a proprietary protein tag that is designed to improve stability of the enzyme in the bloodstream and facilitate uptake by tissues from head to toe. When reinfused into the patient, the gene-modified stem cells are expected to engraft in the bone marrow and produce generations of daughter cells, each carrying the transgene. Those daughter cells are then expected to differentiate into macrophages, microglia, and other components of the immune system and circulate throughout the body and central nervous system, potentially enabling widespread distribution of functional enzyme.

“We believe a lentiviral gene therapy approach is well suited to treat a progressive and pervasive disease such as Hunter syndrome, which affects organs throughout the body and severely impairs cognitive function,” said Geoff MacKay, Avrobio’s president and CEO. “If we treat children early, before their symptoms arise, we hope to prevent the tragic complications that rob these young children of their futures.”

The experimental gene therapy developed by Brian Bigger, a professor of cell and gene therapy at the University of Manchester, United Kingdom, aims to address both physical and central nervous system manifestations of Hunter syndrome. Bigger has published preclinical data demonstrating that the introduction of the transgene with an optimized, proprietary tag has the potential to correct peripheral disease and normalize brain pathology.

“We feel an enormous urgency to bring forward a treatment that may halt this deadly disease in its tracks, before symptoms emerge and before children lose their physical and cognitive skills,” said Bigger.

An investigator-sponsored phase 1/2 clinical trial for Hunter syndrome is expected to enter the clinic in the second half of 2021.

Photo: Geoff MacKay, Avrobio’s president and CEO

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