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Mass General Brigham Gene and Cell Therapy Institute Names First Winners of its Spark Grant Series

Annual grant program debuts with $1.5M being awarded to Mass General Brigham investigators fueling transformational progress in gene and cell therapy

BOSTON, MA (October 18, 2023) – The Mass General Brigham Gene and Cell Therapy Institute, a hub of innovation dedicated to accelerating groundbreaking research, conducting clinical trials and developing FDA-approved treatments, today announced the six winners of its first annual Spark Grant program. The program was created to fund gene and cell therapy projects by Mass General Brigham investigators that demonstrate tangible advancements towards clinical applications and commercialization outcomes, including licensing, partnerships, or new company creation. Grant recipients will receive $250,000 each to continue their work.

This year’s Spark Grant awardees represent innovation at its finest, and their work spans across disease fields such as Huntington’s disease, cancer, chronic pain, leukodystrophies, deafness, and more.

“We are honored to present Spark grants to these truly forward-thinking, boundary-breaking investigators who are dedicating their lives’ work to advancing gene and cell therapies,” said Roger Hajjar, MD, head of the Mass General Brigham Gene and Cell Therapy Institute. “These therapies have the potential to change patients’ lives as well as helping to advance the treatments that we have available for a wide range of diseases and conditions. We congratulate these deserving investigators and look forward to what the future holds for them,” added Nathan Yozwiak, PhD, head of research at Mass General Brigham Gene and Cell Therapy Institute.

The Mass General Brigham Gene and Cell Therapy Institute was established in 2022 to fuel the discovery and development of targeted, transformative treatments that have the potential to cure diseases or halt their progression. The Institute unites more than 400 researchers and clinicians dedicated to advancing gene and cell therapy for first-in-human clinical trials, and ultimately, life-saving treatments for patients.

Applicants were evaluated on numerous criteria including leadership potential in the field of gene and cell therapies, magnitude of the unmet need that the project addresses, technical quality of the proposal, and potential for commercial opportunity.

2023 Spark Grant Awardees

Artur Indzhykulian, MD, PhD, Mass Eye and Ear

Evaluation of human miniPCDH15s in Human Inner Ear Organoids to treat USH1F

Usher syndrome type 1F (USH1F) causes deafness and blindness due to mutations in the protocadherin-15 gene (PCDH15). A simple gene addition therapy for USH1F remains challenging because the PCDH15 coding sequence is too large for adeno-associated virus (AAV) vectors. To overcome this limitation, the team developed “mini”-PCDH15 versions that fit into a single AAV capsid and can restore hearing and balance in mouse models of USH1F. Dr. Indzhykulian will test similarly designed human mini-PCDH15 versions to evaluate their function in human inner-ear organoids. This study will provide a proof-of-concept, preclinical evaluation of human mini-PCDH15s, an essential step for clinical translation.

Casey Maguire, PhD, Massachusetts General Hospital

AAV capsids which efficiently cross the blood brain barrier in primates

Two distinct, yet intertwined major problems are faced by adeno-associated virus (AAV) vectors for global treatment of diseases that affect the brain. First, the standard of care serotype for gene therapy to the CNS, AAV9, crosses the blood-brain barrier (BBB) at relatively low efficiency, so high doses are required for therapeutic benefit. AAV vectors (like other biologics) are costly and difficult to make to treat larger cohorts of patients. The second problem, which is linked to high doses of vector, is activation of the innate and adaptive immune system, which in some cases has led to clinical holds owing to sepsis-like symptoms and even organ failure and death. AAV peptide display libraries to discover novel capsids have been used successfully to achieve efficient transduction of murine CNS after systemic delivery. These proof-of-concept studies show promise that efficient AAV capsids may solve both issues above. The main issue that remains to be solved is obtaining “translationally relevant” AAV capsids that work in humans, as the capsids that have been selected in mice generally do not work in non-human primates (NHPs) and likely won’t work in humans to cross the BBB. The team’s solution is to perform a selection which results in identification of capsids with a high likelihood of crossing the BBB in humans and transducing target neurons.

Robert Manguso, PhD, Massachusetts General Hospital

Rapid identification of nanobody chimeric antigen receptors using nanomice

The team has developed a high-throughput method for generating nanobody-based chimeric antigen receptors (CAR) targeting any antigen. Dr. Manguso’s platform uses a novel strain of mice that produce single-domain (VHH) antibodies. Through immunization of these mice with dendritic cells expressing an antigen of interest, we can induce robust antigen-specific B-cell expansion. From there, the team directly isolates and clones VHH libraries from the immunized mice into CAR vectors and selects for highly functional and specific. This method has been applied to generate novel nanobody-CARs for mesothelin and is currently being used for the development of CARs targeting several additional antigens.

Ricardo Mouro Pinto, M.Sc., PhD, Massachusetts General Hospital

A "One-and-Done" CRISPR therapeutic for multiple repeat expansion diseases

The team is developing a novel CRISPR base editing therapeutic that specifically targets somatic repeat instability, which is a hallmark of disease in multiple repeat expansion disorders, including Huntington’s Disease, Friedreich Ataxia, Myotonic Dystrophy, X-Linked Dystonia Parkinsonism and multiple Spinocerebellar Ataxias. More specifically, we are targeting the DNA repair pathway to prevent pathogenic somatic expansion of disease-causing trinucleotide repeats. This therapeutic reagent would be delivered to disease vulnerable tissues as a single dose to effectively prevent disease onset or halt symptoms' progression.

William Renthal, MD, PhD, Brigham and Women’s Hospital

Nociceptor-specific gene therapy for chronic pain

The team is creating highly specific adeno-associated viruses (AAV) for long-term pain management. The therapy involves using a chemogenetic actuator, activated by an FDA-approved drug, to silence target nociceptors in patients who experience temporary relief from nerve blocks. To avoid anesthesia from off-target neuronal silencing, this approach will leverage gene regulatory elements the lab has identified to promote AAV expression specifically in nociceptors. This one-time therapy aims to provide patient-controlled local analgesia based on existing outpatient interventional nerve block procedures. Moreover, the general approach offers a platform for further development of cell-type and cell state-specific AAVs that may be applicable to other conditions.

Nicholas Todd, PhD, Brigham and Women’s Hospital

Focused ultrasound for delivery of AAV vectors across the BBB

The goal of this project to validate the use of focused ultrasound (FUS) blood-brain barrier (BBB) opening combined with systemic administration of a novel AAV capsid as a platform technology for delivering gene therapies to the brain. FUS can be applied to achieve non-invasive and temporary permeabilization of the BBB in targeted brain regions, allowing normally non-penetrant therapies to reach the brain from systemic circulation. Preliminary data in mice indicates that particularly potent neuronal transfection can be achieved when FUS- BBB opening is combined with a novel AAV capsid, AAV.CPP, engineered for improved penetrance across the BBB. The team will characterize delivery efficacy relative to the current state of the art and demonstrate proof-of-concept gene knock-down/replacement in two clinically relevant diseases. It is anticipated that data from these studies will showcase FUS-BBB opening + AAV.CPP as a leading platform technology for delivering gene therapies to the brain, allowing for several paths to further develop and translate this exciting technology.

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