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Seattle Children’s Researchers Highlight Achievements in Novel Therapies at Gene and Cell Therapy Meeting

April 30, 2024 – Promising cell and gene therapies to treat multiple sclerosis, hemophilia, HIV and more from Seattle Children’s Research Institute’s Center for Immunity and Immunotherapies (CIIT) will be showcased at the American Society of Gene and Cell Therapy’s (ASGCT) Annual Meeting, May 7 to 11, in Baltimore, Maryland.

Eighteen Seattle Children’s researchers, representing the labs of Drs. David Rawlings, Richard James, Carol Miao and Bruce Torbett, are attending this year’s conference. Of those, 10 Seattle Children’s researchers are sharing study results; four are making oral abstract presentations and six will share poster presentations. Last year, 8,000 researchers from around the world attended the meeting. Only a small percentage of submissions are selected for presentations each year.

“Over the last 10 years, multiple CIIT team members have been chosen by the meeting organizers to present our cutting-edge work,” said Rawlings, CIIT director and a professor of pediatrics and an adjunct professor of immunology at the University of Washington School of Medicine. “The competition for such presentation opportunities is fierce, and our continued success highlights the leadership role of our center in this field.”

CIIT researchers’ abstracts highlight rapid progress in expanding novel cell therapy platforms invented at the research institute, including in-vivo application of gene therapy in hemophilia, B cell therapeutics for immune and genetic diseases and engineered regulatory T cells (Tregs) to restore immune tolerance.

Hemophilia Gene Therapy

The Miao Lab team is pursuing safer, more effective treatments for hemophilia, a genetic disorder where the blood doesn't clot properly due to lack of a specific protein called factor VIII (FVIII). Traditionally, patients with hemophilia have been treated with replacement therapy, where the missing clotting factor is infused into the bloodstream. While the infusions help temporarily restore the clotting ability of the blood, reducing the risk of excessive bleeding and related complications, the need for regular injections can be disruptive to daily life and do not address the underlying genetic cause of the condition.

New approaches to gene therapy, which use viral vectors (a noninfectious virus) to deliver the missing gene, face challenges due to safety concerns and pre-existing antibodies against the viral vectors. One important challenge with this form of gene therapy is it often cannot be redosed because the body's immune system may recognize and neutralize the viral vectors upon subsequent exposures, making it difficult to deliver additional doses of the therapy effectively. Miao and her team are studying alternative approaches, which offer a non-viral method for gene transfer without the same limitations associated with viral vectors.

At ASGCT, Miao (on behalf of lead author and former lab member Savannah Lawton) will deliver a talk describing progress using therapeutic ultrasound and tiny bubbles to deliver the missing gene safely in a large-animal model to generate sustained FVIII expression, paving the way for translation of this novel technology in humans.

Dr. Chun-Yu Chen will present on the Miao Lab’s success using lipid nanoparticles to deliver a gene-repairing tool into a small-animal model to correct the mutated FVIII gene. Chen hopes future human application of these lipid nanoparticles will restore normal clotting function, offering potential relief for individuals with hemophilia by mitigating the risk of prolonged bleeding episodes.

Six poster presentations round out the Miao Lab’s contributions. Scott Chao will share two studies (as lead author and on behalf of Lawton) investigating ultrasound-mediated gene delivery in a hemophilia small-animal model to restore FVIII production — a promising, redosable, and noninvasive form of gene therapy.

Ellen Xu’s abstract focuses on the use of CRISPR editing to efficiently target the hemophilia genetic mutation to achieve high editing efficiency with low bystander effects (inadvertent cell death), resulting in a promising hemophilia treatment. Meng-Ni Fan is also reporting on non-viral gene therapy using lipid nanoparticles to deliver FVIII genes with re-dosing capacity and without liver toxicity.

Also from the Miao Lab, Dr. Cameron Rementer has helped develop a way to introduce the FVIII gene into the cells of the bone marrow, a method leading to hemophilia improvement in a large-animal model.

“Over the past few years, we’ve seen the first therapies approved by the FDA using gene and immunotherapies,” Rementer said. “I think this is just the beginning of an exciting period in medicine, and my research could help develop gene therapies for diseases beyond hemophilia.”

Engineered B and T Cells

From the James Lab, Anna Helmers (on behalf of former lab member Dr. Tyler Hill) is sharing progress in developing a new therapeutic modality for single-dose delivery of biologics that leverages engineered plasma cells as therapeutic protein factories. The team has demonstrated long-lived delivery of antiviral antibodies for up to 100 days following a single dose in a small-animal model.

Two research scientists from the Rawlings Lab, Travis Drow and Subhash Tripathi, are giving oral presentations focused on Tregs. Drow and colleagues are using Tregs to treat autoimmune diseases like multiple sclerosis (MS) by targeting specific disease triggers. Using gene-editing techniques, they were able to generate large quantities of these specialized cells, which stopped development of early disease and reduced severity of established disease in a small-animal model of MS.

Tregs play roles in immune tolerance and immunosuppression, impacting autoimmune disorders, solid organ transplantation, and graft vs. host disease (GVHD). The Rawlings team previously developed the EngTreg platform and further added islet antigen specificity to these cells to treat type 1 diabetes. Tripathi is sharing how the lab has now extended the EngTreg platform to add chimeric antigen receptors (CARs) specifically for HLA antigens to these cells. The A2CAR EngTregs show robust in-vitro immune suppressive activity and in-vivo therapeutic efficacy in a humanized small-animal model of GVHD, demonstrating broad therapeutic potential.

Anti-HIV Gene Therapy

The Torbett Lab’s Dr. Chet Ojha is reporting on development of an inexpensive, easy to use, injectable anti-HIV gene therapy to provide a functional cure for individuals living with HIV/AIDS in limited-resource settings. Current HIV therapies are costly and require lifelong treatment. The Torbett team is coupling a protein which binds to HIV and reduces infectivity to gene-delivered expression from B cells, which then become antiviral protein factories in the blood for an individual’s lifetime. In a humanized small-animal models, B cells produced the antiviral protein at levels that would inactivate HIV.

 “These presentations are great career opportunities for our team members,” James said. “Attending conferences like ASGCT helps trainees see their work from a broader perspective and the exposure they get from presenting helps their career advancement.”

— Colleen Steelquist