At the 2022 World Medical Innovation Forum, Mass General Brigham investigators presented their high potential new technologies as part of the “First Look: New Gene and Cell Therapy Technologies” session. Two of these presentations received additional recognition for addressing an unmet need, having clinical impact, scientific strength, and collaboration opportunities. Prizes were awarded to Brigham and Women’s Hospital presenters Anil Chandraker, MD, medical director of Kidney and Pancreas Transplantation and Anna Krichevsky, PhD, associate professor of Neurology.
Cell Therapy Approach Could Replace Immunosuppressive Drugs for Kidney Transplant Patients
Chandraker and his team are working on a new therapeutic approach to replace conventional immunosuppression for patients who receive a kidney transplant. Currently, kidney transplant patients must go on lifelong immunosuppressive medications, which not only increase the person’s risk of infection but are also associated with increased risk of cardiovascular disease, new onset type 2 diabetes and kidney toxicity. Chandraker and his team are developing an alternative form of treatment that takes advantage of a phenomenon that occurs in previously transplanted patients.
“When you transplant a patient, the immune system develops two contradictory responses: we all know about the aggressive immune response that leads it to reject the kidney, but at the same time, the immune system also develops a regulatory response and is trying to accept the kidney,” said Chandraker. “Our idea is that if you can take cells from previously transplanted patients and expand this regulatory population and give it back to the same patient, you should be able to reduce the need for immunosuppression.”
The team has tested their approach, known as Antigen Specific TReg-Enriched cell Lines (ASTRLs), in preclinical models, finding evidence that an infusion of ASTLs could prolong graft survival. To date, the team has taken cells from close to 100 kidney transplant patients, stimulated them with donor antigen and put them through a manufacturing process to develop the therapy ASTRL cells.
The team has established a company, Anya Therapeutics, and is initially focusing on kidney transplants but plans to expand to other organs. They are seeking an additional partner in order to raise a total of $10 million to support the goal of beginning a phase 1 trial next year.
Watch a video of Chandraker’s presentation at the World Medical Innovation Forum.
RNA-Targeting Therapy Takes Aim at Glioblastoma
Despite recent advancements in targeted and immuno-therapies, glioblastoma (GBM) remains one of the deadliest forms of human disease. Even with aggressive surgical resection and chemotherapy, median survival is 15 months — a survival rate that has changed little in 35 years. One of the challenges in developing better treatments is that GBM is a highly heterogenous disease with very few common mutations and markers to target.
“Many in the field believe there is a need for personalized therapies for glioblastoma patients — which may not be practical for an aggressive and fairly rare disease such as GBM,” said Krichevsky. “We believe we have a new strategy today that will combat most of, if not all, GBM cases in adult patients.”
To date, research has focused on protein-coding genes, which make up only two percent of the human genome and only a small portion of which are therapeutically targetable. The “dark matter” or non-coding regions of the genome contain hundreds of thousands of non-coding RNAs. Non-coding RNAs are frequently abnormal in disease — with either too much or too little expressed — especially neurological diseases and cancers.
“RNAs provide tremendous opportunities for novel therapeutics,” said Krichevsky.
Since its inception in 2006, Krichevsky’s lab has focused on one type of regulatory RNA: microRNAs. The lab has generated mounting evidence showing that these microRNAs become dysregulated in cancers and are involved in all aspects of brain tumor pathologies. They also appear to play an important role in neurodegenerative disorders, showing promise as targets for treating Alzheimer’s disease, frontotemporal dementia, progressive supranuclear palsy and more.
For glioblastoma, the lab’s top target is a microRNA known as miR-10b, which becomes abundant in adult GBM patients. In preclinical models of GBM, inhibiting the molecule leads to reduced tumor growth and extended survival. The team is now focused on developing miR-10b inhibitors. They plan to use a lipid nanoparticle to deliver a CRISPR/Cas9 miR-10b-editing system at the time of tumor resection.
Krichevsky’s team has intellectual property on therapeutic miR-10b gene editing for brain tumors and is also pursuing investigations around a separate, neuroprotective microRNA. Moving forward, the team is looking to raise $2.5 to 3 million to complete advanced preclinical studies, manufacture the lipid nanoparticles and their payload and pursue an investigational new drug program to advance their therapeutic candidate.
Watch a video of Krichevsky’s presentation at the World Medical Innovation Forum.