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Molecular brush-conjugated antisense oligonucleotide as a pan-KRAS depletion agent

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R42CA275425-01
Agency Tracking Number: R42CA275425
Amount: $400,000.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: NCI
Solicitation Number: PA21-262
Solicitation Year: 2021
Award Year: 2022
Award Start Date (Proposal Award Date): 2022-09-01
Award End Date (Contract End Date): 2023-08-31
Small Business Information
Natick, MA 01760-6040
United States
DUNS: 117142176
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (617) 373-2000
Business Contact
Phone: (314) 591-9027
Research Institution
360 HUNTINGTON AVE, 177-500
BOSTON, MA 02115-5005
United States

 Nonprofit College or University

Project Summary/AbstractMutant forms of KRAS are a key driver in human tumors but remain partially refractory to therapeutic
intervention. After over three decades of research, only a single inhibitor (sotorasib) targeting a single
mutation (KRASG12C) have reached market. The difficulty for developing small molecule KRAS inhibitors
has heightened the importance of alternative methods targeting the oncogene. One such strategy
involves therapeutic nucleic acids, which make it possible to deplete target proteins that are intractable to
conventional drug modalities. We have developed a novel form of nucleic acid therapeutics, termed
Brushield™ conjugate, which substantially enhances the antitumor activity of antisense oligonucleotides
by elevating in vivo stability, accelerating cellular uptake, and improving plasma pharmacokinetics and
tumor accumulation, allowing for a much lower dosage to be used compared to conventional methods.
The conjugate also suppresses nearly all side effects associated with traditional nucleic acid drugs by
reducing unwanted nucleic acid-protein interactions. The goal of this proposal is to lay the groundwork
for translating the technology towards the clinic. In Phase I, we will optimize the structure of the
Brushield™ conjugate, and enhance current indication using a panel of non-small cell lung cells and
mouse xenograft models. Upon reaching set quantitative milestones, we will subject the conjugate to
more relevant animal models (orthotopic and patient-derived xenograft models), and perform tolerability
and pharmacokinetic studies in mice and monkeys (Phase II). These studies will allow us to pursue an
IND filing at the end of the project.Project Narrative
Mutated KRAS is a highly prevalent oncoprotein driving a number of cancers, but pharmacological inhibition is
limited to only the G12C mutant despite over thirty years of research. Here, we propose to develop an
antisense oligonucleotide-based therapeutic agent which takes advantage of our proprietary delivery
technology. Building upon strong efficacy indication in non-small cell carcinoma mouse models, we will perform
additional structure optimizations, conduct toxicology/pharmacology studies in both mice and non-human
primates, and obtain additional indications in advanced preclinical animal models.

* Information listed above is at the time of submission. *

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