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Development of anti-sense oligonucleotides as a therapeutic for cancer pain through selective block of sodium channel pain targets

Award Number: R44CA247110
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/07/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Development of anti-sense oligonucleotides as a therapeutic for cancer pain through selective block of sodium channel pain targets - Project Summary: Development of anti-sense oligonucleotides as a therapeutic for cancer pain by selectively reducing sodium channel expression Effective treatment of cancer pain is a large unmet medical need, as opioids, the current standard of care lack efficacy and cause addiction. For end-of-life cancer patients and estrogen receptor- positive breast cancer patients with long life expectancy, more effective therapeutic approaches for pain are needed. Antisense oligonucleotides (ASOs) bind to and induce degradation of RNA transcripts with specific sequences, enabling selective protein knockdown (KD) with long duration of action (weeks or months), to deliver long-term relief. ASOs can also be used in combination, to reduce the expression of multiple proteins for increased efficacy. As a modality, ASOs have been successfully applied in the clinic to treat severe neurological disease. We target the voltage gated sodium channels (Navs) selectively expressed in dorsal root ganglion neurons (Nav1.7, Nav1.8 and Nav1.9), which are implicated in pain transmission and specifically in cancer pain. Reduction of channel expression aims to overcome the limitations of small molecule state-dependent channel blockers, if the channel should be blocked in a state-independent manner for efficacy. Preliminary results with our designed ASOs show >70% mRNA KD for several Navs in rat dorsal root ganglion sensory neurons (DRGs). We apply a novel platform to design ASOs for specific knockdown of Nav channels. For pain targets and indications, QuellTx also has an exclusive worldwide license to breakthrough technology: (i) An in vitro cellular model for cancer pain (developed through SBIR funding by NCI), where primary DRG neurons are bathed in a physiologically-relevant mixture of inflammatory mediators secreted by tumors, or ‘cancer-SPARC’. The SPARC- treated neurons become hyperexcitable, mimicking the cellular pain response. (ii) An all optical electrophysiology high throughput readout for neuronal excitability (Optopatch), allowing recordings from 100s of individual neurons in parallel with high temporal resolution. This platform enables us to determine the impact of modulating expression of Nav1.7, 1.8 and 1.9, alone or in combination, on the pain-in-a-dish phenotype. In Phase I we propose to leverage our ASO design capabilities, combined with the breakthrough technology to: (a) identify ASOs for selective modulation of expression of Nav channel pain targets and (b) determine the combination of ASOs and %mRNA knock down for maximal phenotypic effect in vitro. We will select ASOs that efficiently knockdown Nav channels and reverse the pain phenotype induced by cancer-SPARC. In Phase II we will determine the PK/PD (%mRNA KD) in rats, and the % mRNA KD needed for efficacy in a rat model of cancer pain, while optimizing human cross-reacting with cynmolgous monkey (cyno) ASOs for efficacy in human DRG neuronal models of pain. Our ultimate goal is to advance optimized ASOs to IND enabling toxicity studies in rat and cynos, leading to a therapeutic to treat cancer pain in patients.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	QUELLTX INC	179 SIDNEY ST	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Treatment Research	001	3	7/24/2024	NON-COMPETING CONTINUATION	$0
2024	2022	QUELLTX INC	179 SIDNEY ST	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Treatment Research	000	3	12/21/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $995,305 )
2022	2022	QUELLTX, INC.	179 SIDNEY ST	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Treatment Research	001	3	5/26/2022	NON-COMPETING CONTINUATION	$995,305
2022	2020	QUELLTX, INC.	179 SIDNEY ST	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Treatment Research	000	1	5/13/2022	NEW	$0
														Subtotal = $995,305

Issue Date FY: 2021 ( Subtotal = $1,000,001 )
2021	2021	QUELLTX, INC.	179 SIDNEY ST	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Treatment Research	001	2	5/25/2021	EXTENSION WITH OR WITHOUT FUNDS	$1,000,001
2021	2020	QUELLTX, INC.	179 SIDNEY ST	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Treatment Research	000	1	4/28/2021	NEW	$0
														Subtotal = $1,000,001

Issue Date FY: 2020 ( Subtotal = $300,728 )
2020	2020	QUELLTX, INC.	179 SIDNEY ST	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Cancer Treatment Research	000	1	9/7/2020	NEW	$300,728
														Subtotal = $300,728

Grand Total All Awards = $2,296,034

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Development of anti-sense oligonucleotides as a therapeutic for cancer pain through selective block of sodium channel pain targets

Award Number: R44CA247110

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/07/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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