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Therapy of Pulmonary Diseases with Peptide-Oligonucleotide Conjugates and Small Molecule Enhancing Compounds

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 2R44TR002692-02
Agency Tracking Number: R44TR002692
Amount: $1,726,954.00
Phase: Phase II
Program: SBIR
Solicitation Topic Code: 100
Solicitation Number: PA19-272
Solicitation Year: 2019
Award Year: 2020
Award Start Date (Proposal Award Date): 2020-08-01
Award End Date (Contract End Date): 2022-07-31
Small Business Information
Chapel Hill, NC 27514-7631
United States
DUNS: 079581510
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (919) 619-2001
Business Contact
Phone: (919) 619-2001
Research Institution

Antisense oligonucleotides (ASOs), siRNA and splice switching oligonucleotides (SSOs) all have immense
potential as therapeutic agents, potential that is now being validated as oligonucleotides enter the clinic. SSOs
in particular possess great therapeutic flexibility since they can be used to increase, decrease or alter the pattern
of mRNA expression. However, progress in oligonucleotide-based therapeutics has been limited by the difficulty
in delivering these complex molecules to their sites of action in the cytosol or nucleus of cells within specific
tissues. There are two aspects to the delivery problem. The first is that most types of oligonucleotides have poor
uptake into non-hepatic tissues such as the lung. The second is that much of the oligonucleotide that is taken
up by cells is entrapped in endosomes where it is pharmacologically inert. Initos Pharmaceuticals has developed
a dual approach that overcomes both aspects of the oligonucleotide delivery problem, focusing particularly on
SSOs. First, we make use of SSOs comprised of peptide-morpholino oligonucleotide conjugates (P-PMOs) that
have greater cell uptake and a broader tissue distribution than conventional oligonucleotides. Second, Initos has
addressed the intracellular delivery issue by creating novel proprietary oligonucleotide enhancing compounds
(OECs) that mobilize all types of oligonucleotides from endosomes thus significantly increasing their therapeutic
While the P-PMO/SSO+OEC combination is a platform technology applicable in many therapeutic contexts, this
proposal focuses on two challenging problems in pulmonary disease. First, we will address the correction of
splicing mutations in cystic fibrosis patients who are refractory to current therapies including modulator drugs.
Second, we will use the P-PMO/SSO+OEC combination to reduce the hypersecretion of mucins MUC5AC or
MUC5B that is characteristic of several major airway diseases including asthma, cystic fibrosis (CF), chronic
obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF).
During our current Phase I STTR we established proof of concept for the P-PMO/SSO+OEC technology by
showing: (a) correction of splicing in lungs in a murine reporter model; (b) correction of splicing and restoration
of function in CF patient-derived differentiated airway cells; (c) dramatic reduction of MUC5AC expression in
human cells. In our Phase II SBIR application we propose IND-facilitating development of our unique P-
PMO/SSO+OEC technology. The goal is to identify P-PMO/SSO+OEC entities that are highly efficacious and
minimally toxic by optimization of composition, dose, timing and route of administration. The deliverables for the
proposed project are the development for pre-IND evaluation of P-PMO/SSO+OEC entities for therapy of a CF
splicing mutation and for reduction of MUC5AC or MUC5B hypersecretion.NARRATIVE
This proposal describes a novel technology to facilitate the therapeutic use of oligonucleotides by improving their
intracellular delivery. We will use a special type of oligonucleotide called a P-PMO in combination with a small
molecule termed an OEC. We will use the P-PMO+OEC combination to correct an RNA splicing defect in certain
patients with cystic fibrosis. We will also use this approach to reduce over-production of mucus that is a problem
in many pulmonary diseases.

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

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