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UMass Chan Medical School has established the , ushering in the next phase of gene therapy development to accelerate new treatments for rare genetic diseases.

The institute, led by Miguel Sena-Esteves, PhD, leverages UMass Chan Medical School’s extensive experience in researching and developing gene therapies for early-stage clinical trials. Currently in clinical trials are therapeutics for Tay-Sachs disease and amyotrophic lateral sclerosis (ALS). The institute is specifically focused on increasing the number of and reducing the costs associated with human gene therapy clinical trials for rare genetic diseases.

This week, an important milestone in human gene therapy was reached. Terence R. Flotte, MD, the Celia and Isaac Haidak Professor, executive deputy chancellor, provost and dean of the T.H. Chan School of Medicine, Dr. Sena-Esteves, associate professor of neurology and a member of the Horae Gene Therapy Center at UMass Chan, and colleagues reported on the first ever gene therapy for infantile Tay-Sachs to reach clinical trials in humans. Published in Nature Medicine, the  shows that an adeno-associated virus (AAV) gene therapy can be safely administered to infants and further, it can increase enzymatic activity and improve imaging biomarkers. Heather Gray-Edwards, DVM, PhD, assistant professor of radiology, is a part of the development team for the research discoveries, in conjunction with Douglas Martin, PhD, professor of anatomy, physiology and pharmacology at Auburn University College of Veterinary Medicine.

“One of the things we learned from doing the Tay-Sachs study is that there are a number of fixed activities that all potential genetic therapeutics have to go through in order to move from the lab to the clinic,” said Sena-Esteves. “The cost of these activities keeps going up at a pace that would exclude rare diseases from potential gene therapies. Having all the infrastructure, together, in the Translational Institute for Molecular Therapeutics, will make it easier for UMass Chan investigators to bring new therapeutics to clinic for these forgotten diseases that have difficulty attracting investment from outside entities.”

In December 2021, Robert H. Brown Jr., DPhil, MD, the Leo P. and Theresa M. LaChance Chair in Medical Research and professor of neurology; Jonathan Watts, PhD, associate professor of RNA therapeutics; and colleagues at UMass Chan , the first trial of its type. Also, UMass Chan has received pre-investigational new drug (IND) clearance from the U.S. Food and Drug Administration for the first ever trial for late onset Tay-Sachs.

The institute includes infrastructure to assist investigators with manufacturing, regulatory matters and IND-enabling studies needed to conduct first-in-human clinical trials. Importantly, UMass Chan has GMP and GMP-like manufacturing facilities to produce the necessary biologicals needed for proof-of-concept and pilot clinical trials. Pilot trials require smaller volumes while still adhering to manufacturing standards for application in humans. Due to a lack of facilities specializing in small-scale production of therapeutics, such as the type needed for pilot clinical trials, sourcing the manufacturing of therapeutics can be time-consuming, expensive and difficult.

“Instead of investigators having to do all the legwork on their own, they will have access to a network of resources that will allow them to do more in a much shorter time frame,” said Sena-Esteves.

UMass Chan will seek philanthropic support to fund preclinical research, manufacturing and the investigational new drug costs associated with moving potential gene replacement therapeutics from the lab to the clinic.

There are more than 7,000 known rare diseases and about 250 more are identified annually. This number is likely to continue to increase as more human diseases are genetically characterized and identified. Although the definition of a rare disease differs around the world, the U.S. Food and Drug Administration defines it as a malady that affects fewer than 200,000 people in the United States. Some of the more ultra-rare diseases may only afflict 40 to 50 people worldwide.

Much of the expertise that will be leveraged by the Translational Institute for Molecular Therapeutics is evident in the current Nature Medicine study.

“This is a proof-of-concept; a first step to developing a gene therapy for Tay-Sachs,” said Sena-Esteves. “The two children treated tolerated the gene therapy well and showed no adverse effects. Though the dose administered was sub-therapeutic and far from where it needs to be to have a profound impact, nonetheless, there was some indication of increased molecular activity.”

Tay-Sachs is an inherited disease caused by a deficiency of hexosaminidase A (HEXA), an enzyme that helps break down fatty substances in cells. These fatty substances, called gangliosides, build up to toxic levels in an infant’s neurons and affect the function of the nerve cells in the brain and spinal column. Children with Tay-Sachs inherit a faulty copy of the HEXA gene from both parents.

Typically diagnosed in the first 12 to 14 months of life, Tay-Sachs has symptoms that include a loss of the ability to sit, difficulty swallowing, seizures and loss of other developmental milestones. Tay-Sachs is a rapidly progressive disorder, and the median life expectancy is approximately 3 to 4 years. There is no effective treatment.

The UMass Chan trial was designed to evaluate the safety of an AAV gene therapy. The therapeutic was administered to a 30-month-old infant and a 6-month-old infant with infantile or juvenile GM2 gangliosidosis. The treatment was delivered surgically to the brain and via injection to the cerebrospinal fluid.

Neither trial participant reported any adverse effects from the injections. Western blots and enzymatic activity markers indicated an increase in HEXA activity. Both subjects reported disease stabilization at three months post-injection. The first patient, now 5 years old, remains seizure free while on the same anticonvulsive therapy as pretreatment.

“This is an encouraging first step,” said Sena-Esteves. “However, it’s only a fraction of the amount needed to produce a therapeutic impact. To have an impact on disease progression, we’d have to increase the dose by as much as tenfold.”

In 2018, Sio Gene Therapies (formerly known as Axovant), licensed exclusive worldwide rights from UMass Chan for the development and commercialization of gene therapy programs for infantile or juvenile GM1 gangliosidosis and GM2 gangliosidosis, including Tay-Sachs and Sandhoff diseases. A multipatient, Phase I/II study for AXO-AAV-GM1 is underway by Sio Gene. It is the only gene therapy in clinical development for both infantile (type 1) and juvenile (type 2) GM1 gangliosidosis.