New hope for Tay-Sachs disease

The death sentence of Tay-Sachs disease is being challenged by a new gene therapy formulated at UMass Medical School. Tay-Sachs, a fatal genetic neurological disorder that destroys nerve cells in the brain and spinal cord, affects about 1 in 300,000 infants in the United States.

Heather Gray- Edwards, PhD, DVM, spends a moment with Madelyn and Mollie Ronaldson at the 2018 National Tay-Sachs & Allied Diseases Association conference. Both girls have juvenile Sandhoff, a lysosomal storage disease similar to Tay-Sachs.

Working under an “expanded access” protocol approved by the U.S. Food and Drug Administration, a research team at UMMS has administered the new gene therapy to two children with Tay-Sachs—the first was treated in the fall of 2018 and the second in the summer of 2019. Both children have tolerated the gene therapy well and are being followed by a clinical research team from the medical school.

“We all realize there is still a long way to go, but taking this new therapy to patients is an important step forward,” said Miguel Sena-Esteves, PhD, associate professor of neurology, member of the Horae Gene Therapy Center, and the principal investigator of the Tay-Sachs gene therapy program at UMMS.

The new gene therapy is the result of more than a decade of collaborative research by the Sena-Esteves lab and a team at Auburn University led by Douglas Martin, PhD, professor of anatomy, physiology and pharmacology at Auburn’s College of Veterinary Medicine. It’s been an intense effort of scientific discovery and molecular engineering, with instances of rapid progress tempered by disappointing setbacks. Most importantly, Dr. Sena-Esteves said, it is a story of perseverance, both among the research teams and members of the Tay-Sachs community who saw the potential of the gene therapy and funded the research at critical junctures. In 2018, their research approach moved into further clinical development when Axovant Gene Therapies, a Swiss-based company with U. S. operations, licensed the discoveries.

“We have been waiting for this moment for a long time,” said Rick Karl, president of the Cure Tay-Sachs Foundation, which has been a financial supporter of the research. “The science and technology have finally caught up with what we have known for years about the genetics of the disease. The work Miguel and his colleagues are doing is the most promising treatment we have seen so far.”

Tay-Sachs is a cruel and insidious disease. Children with the disease appear healthy at birth, but the destruction of their neurons has already begun. Symptoms develop around 6 months of age, first apparent when children start missing developmental milestones. Muscle function and cognitive abilities decline. By age 3, most are unable to move or breathe on their own. Few reach their fifth birthday.

Alisha Gruntman, DVM, PhD, assistant professor of pediatrics, with Dean Terence R. Flotte in their gene therapy lab. Dr. Gruntman’s work on optimizing delivery methods for gene therapy vectors for different diseases shows the rapid progress and maturation of the field of therapeutic gene replacement.

The new therapy delivers a working copy of the HexA gene directly into the brain and spinal cord. That new gene is taken up by neurons and directs production of the HexA enzyme, which is then released and spreads throughout the central nervous system for use by other cells. In animal studies, the new gene did its job well, and the enzyme it produced functioned properly, helping neurons clear out the waste products.

While the therapeutic impact for the two children who have been treated is being studied, Axovant expects to launch a multipatient Phase I/II clinical trial of the Tay- Sachs gene therapy in 2019.

Axovant also licensed a gene therapy for a similar disease, GM1 gangliosidosis, developed by the UMMS and Auburn teams, and is now funding a Phase I/II clinical trial being conducted at the National Institutes of Health. Until now, there has been no treatment, other than supportive care, for those with these genetic disorders. Now, there is hope that change is on the horizon.

“The work done by this collaborative team, to develop a firstever gene therapy for Tay-Sachs, shows what translational research is all about,” said Terence R. Flotte, MD, the Celia and Isaac Haidak Professor of Medical Education, executive deputy chancellor, provost and dean of the School of Medicine at UMass Medical School, who is the clinical investigator for the Tay-Sachs expanded use trial. “It is scientists and physicians working together to address medical conditions that can be truly tragic for patients and families.”

The gene therapy approach that is making this possible is based on the technology of viral vectors— engineering a harmless and naturally occurring virus called an adenoassociated virus (AAV) to deliver a therapeutic gene.

AAV infects many different tissues and organs, but does not cause disease. Like all viruses, AAV has an outer shell that encloses its genes. On the surface of the shell are elements that help guide the virus to a target cell. When the virus gets into a cell, the shell opens and releases its genes, which in turn use the host cell’s machinery to make more copies of the virus.

“Viruses have evolved over millions of years to do one thing—deliver genetic material to a cell so they can replicate,” Sena-Esteves said. “We use what evolution has given us as a starting point, then engineer the delivery mechanisms and the genetic payload.”

How it works

To understand how a viral vector works, think of shopping online and getting a package delivered to your home. In that process, you select a specific product, which is then packaged in a standard size cardboard box. An address label is affixed to the box and the package is sent for delivery.

The delivery truck hits the road carrying many boxes that all look very much the same. The only difference for your order is the information on the address label that tells the driver where to leave the box. When delivery is completed, you bring the box inside, open it and use whatever you bought.

In this analogy, the box is the AAV’s outer shell. The address label contains surface elements on the virus shell that guide the AAV to enter certain cells. The product inside the cardboard box is a good copy of the gene required to make the enzyme missing in Tay-Sachs patients, and no virus genes are carried along.

Populations at risk

Tay-Sachs was first described in the 19th century among the children of Eastern European Jews—specifically, Ashkenazi Jews—who remain the population at greatest risk. According to the National Human Genome Research Institute of the NIH, approximately 1 in 27 adult Ashkenazi Jews are carriers of the disease.

In general, people have two copies of every gene—one each inherited from their mother and father. A person with one copy of the Tay- Sachs gene, and a healthy copy, will be a carrier but will not develop the disease. Tay-Sachs arises when both parents are carriers and both pass on the faulty gene to their children.

Eric Horn, Foreground, a veterinary student from the Cummings School of Veterinary Medicine doing an internship at UMMS, identifies microscopic inflammation markers in brain scans of mice with a disease similar to Tay-Sachs, along with Miguel Sena-Esteves; postdoctoral associate Rita Batista, PhD; Heather Gray-Edwards.

In the 1970s, a blood test was developed to identify the Tay-Sachs gene. For generations, the test has been recommended for Jewish couples prior to starting a family.

“The Jewish community has done a terrific job of, essentially, screening this disease out,” Karl said. “There are very few new Jewish cases of Tay-Sachs today. The big problem is that a misperception persists, even still among many physicians, that Tay-Sachs is only a Jewish disease. It is not.”

Magnetic resonance images of the brains of Tay-Sachs disease sheep show differences between normal sheep (A and D), untreated sheep (B and E) and sheep treated with a low dose of gene therapy (C and F). Significant improvements in the presence of disease in Jacob sheep, which have a gene mutation that causes Tay-Sachs disease, was an important precursor to human trials.

Karl doesn’t approach this issue casually. His daughter Krystie Anna died of Tay-Sachs in 2015. Neither Karl, nor his husband, Bruce, nor the egg-donor for the surrogate pregnancy is Jewish. Yet they were carriers. “We were not tested, because we didn’t realize we were at risk,” Karl said.

Current research shows that people of Cajun, French-Canadian and Irish descent are also at higher risk for Tay-Sachs, with approximately 1 in 50 adults carrying the gene. The incidence of disease is also now rising in Brazil, Argentina and in some Middle Eastern countries as awareness and diagnosis of the disease improves. Overall, 1 in 250 people in the general global population carry the Tay-Sachs gene. There are approximately 30 new cases in the United States each year, and an estimated 400 to 700 cases world-wide.

“Whenever I get the chance to speak with groups of young people, I urge them to get tested,” Karl said. “It’s a simple blood test. It costs about $100. And it can prevent this disease.”

Cat and mouse

Tay-Sachs is one of 40 similar rare genetic disorders called lysosomal storage diseases. There are minor biologic differences in each, but all have a similar profile: a missing enzyme disables a nerve cell’s ability to remove or recycle waste products. The result is a loss of motor and neurological function.

The collaboration between Sena-Esteves and Martin arose serendipitously at a gene therapy scientific meeting in 2006. At that time, Sena-Esteves was working on the lysosomal storage disease GM1 gangliosidosis. He was presenting a poster on his lab’s recent discovery of an effective method to deliver a lysosomal enzyme throughout the brain in mice.

Before the meeting began, Sena- Esteves was reading through the program and noticed a researcher from Auburn University was presenting a poster about his work on GM1 in cats, in which a naturally occurring form of the disease was discovered in the late 1970s. When the poster session began, the two GM1 posters were placed opposite each other and the authors struck up a conversation. “It was just by chance that we were at that meeting together, but it was obvious right away that we could work together,” Sena-Esteves said.

The Sena-Esteves lab worked on engineering the viral vectors to enhance delivery and therapeutic impact; the Martin lab would then test those vectors in the cat model and analyze the results. That information would help Sena- Esteves with further development of the vectors. “We work mostly independently, but it has been a great collaboration. We bring different strengths to the project and we respect each other’s opinions,” Sena-Esteves said.

It was through this collaboration that Sena-Esteves and Martin expanded the scope of their research to include Tay-Sachs, after a meeting with Sophia Pesotchinsky, who emigrated to the United States in 1976 with her husband, Leon, and infant daughter, Vera.

Pesotchinsky is a chemical engineer by training and became a successful serial entrepreneur, building several medical device companies. Her husband, who passed away in 2018, was a professor of mathematics at the University of California. When Vera was diagnosed with a late-onset form of Tay-Sachs in 2000, her mother threw herself into the cause.

“I quit my company. I needed to have time to learn about the disease,” she said. “This was the pre-Google era, so I spent a lot of time in the library and started to make phone calls. By 2007, I pretty much knew everybody who was working in the field.”

Pesotchinsky learned about Sena-Esteves and his GM1 gene therapy work from Martin—and promptly reached out. After an initial phone call, she flew to Massachusetts to meet with him and to urge him to include Tay-Sachs in his work. She also asked Sena-Esteves, Martin and another researcher who ran a lab at Boston College to unify their efforts on Tay-Sachs.

Rita Batista, PhD, with Toloo Taghian, PhD a postdoctoral fellow in the laboratory of Heather Gray-Edwards.

Ryan Senecal, a research technician in the Esteves lab, foreground, with Miguel Sena-Esteves.

“I am an engineer, so my inclination is always to look for efficiencies when trying to solve problems,” Pesotchinsky said. “I knew that we couldn’t have three people working independently—there wouldn’t be enough money to go around. We had to get them together.”

The result was the formation of the Tay-Sachs Gene Therapy Consortium, with Sena-Esteves and Martin as founding members. The consortium has played an important role in coordinating the field and raising money to support research. Pesotchinsky remains on the consortium’s board and is also a leader in the National Tay-Sachs & Allied Diseases Association, which funds research to find a cure for Tay-Sachs, Sandhoff, Canavan, GM1 and related diseases. “I do this, because I don’t have any choice,” she said. “My daughter is losing the ability to walk and to talk. Her quality of life is going down with every neuron lost. We are in competition with time, so I have to keep fighting.”

Jacob sheep

As the gene therapy research continued in animal models of the disease, a naturally occurring form of Tay-Sachs was discovered in Texas, in a herd of an ancient breed of sheep called Jacob sheep. That created an opportunity to test the emerging therapy in a larger animal, with a brain closer in size and complexity to humans.

Heather Gray-Edwards, PhD, DVM, now an assistant professor of radiology at UMass Medical School, was working as a postdoctoral fellow in the Martin lab at Auburn when the Jacob sheep model was discovered. The team quickly moved to test their latest AAV vectors and gene therapy in the sheep, with Dr. Gray-Edwards taking the lead on administration of the therapy and the analysis of the results.

A breeding flock of Jacob sheep was established at Auburn. Sheep that were born with the Tay-Sachs equivalent were studied and some were treated with the new therapy. “Every single animal we treated had some improvement,” Gray-Edwards said. “Even at low doses, we saw therapeutic effects, which is quite amazing.”

The treated sheep were able to walk better and lived nearly twice as long the untreated sheep. Beyond the efficacy of the gene therapy, the sheep studies also helped refine the treatment plan proposed for the human trials.

Gray-Edwards found that delivering the gene therapy only to the sheep brain was not sufficient, because the therapeutic enzyme did not spread throughout the entire spinal cord, as it had done in the cat and mouse models. “Based on the sheep studies, we added the spinal cord delivery to the expanded access trial. All of the kids who may be treated in the future will get that as well to overcome the limitation,” Gray-Edwards said.

Meanwhile, the research team continues to explore the science and refine the technology, working on a second-generation Tay-Sachs gene therapy and collaborating with others in the Horae Gene Therapy Center to extend the AAV platform to treat other neurological diseases.

Through it all, the children with Tay-Sachs are never far from mind. “We have been working on this for a long time. I think about all the children who have died since we began. And I hold on to hope for the children who are living with Tay- Sachs today, that we may be able to help them in the coming years,” Sena-Esteves said.

By Michael Cohen

@UMASSMED MAGAZINE | 19