Nanoparticles targeting CRISPR to cancer

Boston Children’s team’s system targets gene editing therapies to triple negative breast cancer cells

A Boston-based team has devised a tumor-targeted, flexible nanoparticle that could yield CRISPR gene editing therapies for cancers including triple-negative breast cancer.

Marsha Moses, a professor at Harvard Medical School and director of the vascular biology program at Boston Children’s Hospital, told BioCentury that TNBC is difficult to treat because traditional tumor targets are inaccessible. She added that gene editing approaches including CRISPR haven’t been successfully applied to TNBC.

More broadly, gene editing in oncology -- an emerging treatment modality at the 2019 American Association for Cancer Research (AACR) meeting -- has focused on engineered cell therapies. At AACR, only one group described editing tumor cells; the group used an adenoviral vector to deliver a CRISPR payload to non-small cell lung cancer cells in mice (see “AACR Moves in a Myeloid Direction”).

According to Peng Guo, an instructor in Moses’ lab, viral vectors for gene therapy delivery are limited in the size of payload they can carry and have safety concerns. Cationic nanoparticles, including lipid nanoparticles, typically lack tissue specificity and are associated with cytotoxicity. Additionally, phagocytosis frequently limits efficacy by destroying the nanoparticles and their payloads.

In a Proceedings of the National Academies of Sciences paper published Monday, Moses’ team described a new delivery system, dubbed “nanolipogels,” consisting of non-cationic lipid bilayers that surround hydrogel holding plasmids that encode CRISPR payloads. Antibodies against tumor surface antigens linked to the lipid enable targeted delivery to tumor cells.

“We can vary the payload of the nanolipogel to deliver whatever we want to deliver.”

Marsha Moses, Boston Children’s and Harvard

Guo said that the nanolipogel’s lack of rigidity improves efficacy by fusing the particles with cell membranes and diverting them from phagocytic elimination. Moreover, the particles’ lack of positive charge reduces cytotoxicity by preventing the particles from lysing non-targeted cells. Cytotoxicity further decreases as the antibodies enable them to avoid delivery to normal tissues, he said.

In a proof-of-principle experiment, nanolipogel particles displaying antibodies against ICAM-1 -- present on TNBC cells but not other breast cancer cell types -- encasing plasmids for CRISPR-mediated excision of oncogene LCN2 reduced tumor volume by 77% in a mouse TNBC model and led to an editing efficiency of about 81%.

Serum biomarker and histological staining showed no toxicity in the liver, kidney and spleen.

Moses said her lab has developed a platform for identifying and validating optimal target surface antigens for different cancer types. “We can vary the payload of the nanolipogel to deliver whatever we want to deliver. So we’re definitely using this approach for other types of cancers,” she added.

Targets: LCN2 (NGAL) - Lipocalin 2; ICAM-1 (CD54) - Intercellular adhesion molecule-1

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