Therapy Areas: Cardiovascular
Avrobio Expands Lentiviral Gene Therapy Pipeline with Program for Hunter Syndrome
5 October 2020 - - US-based clinical-stage gene therapy company Avrobio, Inc. (NASDAQ: AVRO) has inked an exclusive, worldwide license agreement and a collaborative research funding agreement with The University of Manchester for an investigational lentiviral gene therapy for mucopolysaccharidosis type II (MPS II), or Hunter syndrome, a rare and deadly lysosomal disorder that primarily affects young boys, the company said.

Hunter syndrome, which affects an estimated one in 100,000 to one in 170,000 males worldwide, causes devastating complications throughout the body and brain, including severe cardiac and respiratory dysfunction, skeletal malformations and hearing impairment.

Children with severe cases of Hunter syndrome typically show early symptoms in their toddler years and begin to regress developmentally around age six, losing basic motor skills and cognitive function.

The current standard of care is weekly enzyme replacement therapy, which can delay some complications but does not halt overall progression of the disease and has not been demonstrated to address cognitive issues.

Even with ERT, people with Hunter syndrome face life-limiting symptoms and a significantly reduced life span.

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

The program was developed by Brian Bigger, Ph.D., a professor of cell and gene therapy at the University of Manchester, UK Prof.

Bigger has published preclinical data demonstrating that the introduction of the transgene with an optimised, proprietary tag has the potential to correct peripheral disease and normalise brain pathology.

Primary investigators for the Phase 1/2 clinical trial will be Prof. Robert Wynn, M.D., consultant pediatric hematologist at the Royal Manchester Children's Hospital, and Dr. Simon Jones, MBChB, consultant pediatric physician for inherited metabolic diseases at the Willink Unit, Saint Mary's Hospital and the Manchester Centre for Genomic Medicine.

The investigational gene therapy, which will be called AVR-RD-05, 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.

Avrobio's other investigational gene therapies for lysosomal disorders are being evaluated in a Phase 1 and Phase 2 clinical trial for Fabry disease, a Phase 1/2 trial for cystinosis and a Phase 1/2 trial for Gaucher disease.

In addition, the company is advancing a preclinical program in Pompe disease.

The University of Manchester's technology transfer office, the University of Manchester Innovation Factory and Avrobio have negotiated an exclusive, worldwide license agreement to the technology and a collaborative research funding agreement.

Under the license 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.

Additionally, under the collaborative research funding agreement, Avrobio will cover budgeted Phase 1/2 clinical trial costs.

Hunter syndrome, also known as mucopolysaccharidosis type II (MPS II), is a lysosomal disorder caused by a mutation in the IDS gene that leads to a deficiency of the lysosomal enzyme iduronate-2-sulfatase, 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.

The current standard of care is weekly enzyme replacement therapy, which may delay some symptoms but does not halt the overall progression of disease and does not cross the blood-brain barrier, an intricate web of protective tissue that selectively prevents macromolecules from entering the brain.

Even with treatment, people with Hunter syndrome face life-limiting symptoms and a significantly reduced life span.

The disorder affects an estimated one in 100,000 to one in 170,000 males worldwide; about two-thirds of cases have an early, severe progressive form.
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