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Correction of Splicing Defects in Cystic Fibrosis with Peptide-Oligonucleotide Conjugates and Small Molecule Enhancing Compounds

Award Number: R41TR002692
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2020

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Correction of Splicing Defects in Cystic Fibrosis with Peptide-Oligonucleotide Conjugates and Small Molecule Enhancing Compounds - ABSTRACT The pathogenesis of Cystic Fibrosis (CF) is caused by mutations in the gene for CFTR, a cAMP activated chloride channel that regulates salt and water transport in epithelial tissues, especially those in the airways. Recent progress has resulted in small molecule therapeutic agents that partially correct defects in the CFTR protein due to certain mutations. However, in a substantial fraction of CF patients the disease is due to splicing defects in the CFTR gene that cannot be directly addressed using small molecule therapeutics. In these patients splice switching oligonucleotides (SSOs) may provide a means to correct the underlying molecular defect and permit expression of fully functional CFTR protein. SSOs have recently enjoyed success in treating other genetic disorders in patients, including Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA); however they have not yet been applied to CF. Although this concept is appealing, the effective delivery of oligonucleotides remains a problem for the entire field of oligonucleotide based therapeutics and may be especially challenging in the airways. Thus we intend to use a novel dual approach to attain effective delivery of corrective SSOs to airway epithelial cells. First we will make use of oligonucleotides that are chemically conjugated to short, positively charged peptides that augment cellular uptake of the oligonucleotide. In particular we will use P-PMOs in which the peptide (P) is conjugated to an uncharged, non-toxic morpholino (PMO) oligonucleotide. Second, we will make use of recently discovered oligonucleotide enhancing compounds (OECs) i.e. small molecules that release oligonucleotides from unproductive entrapment in endosomes thus potentiating their action. The current proposal is designed to be a proof of concept for this dual delivery approach via testing of P-PMOs and OECs in CF-relevant cell culture and animal model systems. Validation of this concept would be a key step in developing a novel therapy for a significant cohort of CF patients and may have broader ramifications for use of oligonucleotides in other airway diseases. ! 1!


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: 2022 ( Subtotal = $11,710 )
2022	2019	INITOS PHARMACEUTICALS LLC	408 LYONS RD	CHAPEL HILL	NC	27514	ORANGE	USA	National Center for Advancing Translational Sciences	000	1	9/26/2022	NEW	$11,710
														Subtotal = $11,710

Issue Date FY: 2021 ( Subtotal = -$11,710 )
2021	2019	INITOS PHARMACEUTICALS LLC	408 LYONS RD	CHAPEL HILL	NC	27514	ORANGE	USA	National Center for Advancing Translational Sciences	000	1	5/29/2021	NEW	-$11,710
														Subtotal = -$11,710

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	INITOS PHARMACEUTICALS LLC	408 LYONS RD	CHAPEL HILL	NC	27514	ORANGE	USA	National Center for Advancing Translational Sciences	000	1	7/17/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $224,931 )
2019	2019	INITOS PHARMACEUTICALS LLC	408 LYONS RD	CHAPEL HILL	NC	27514	ORANGE	USA	National Center for Advancing Translational Sciences	001	1	7/1/2019	NEW	$0
2019	2019	INITOS PHARMACEUTICALS LLC	408 LYONS RD	CHAPEL HILL	NC	27514	ORANGE	USA	National Center for Advancing Translational Sciences	000	1	1/15/2019	NEW	$224,931
														Subtotal = $224,931

Grand Total All Awards = $224,931

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Correction of Splicing Defects in Cystic Fibrosis with Peptide-Oligonucleotide Conjugates and Small Molecule Enhancing Compounds

Award Number: R41TR002692

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2020

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