Vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's disease related dementias(ADRD) significantly contribute to the 47 million people world-wide who suffer with dementia. This number isestimated to increase to over 130 million people by 2050. Several studies have shown that VCID and conversionto ADRD are strongly correlated with vascular disease, inflammation and decreased cerebral brain blood flow.The relationship between vascular disease, cognitive function and progression to dementia and possible ADhave been recently reviewed 1. These authors successfully make the case for a close relationship betweencardiovascular risk factors and risk for VCID and ADRD. Furthermore, conversion rates of VCID to dementiahas been reported to be within 40-46% within 5 years of diagnosis of VCID. To date, there are no approvedtherapies for VCID. ProNeurogen has been working to develop novel Angiotensin 1-7 (Ang-1-7) formulations totreat cognitive impairment in patients at for risk ADRD and VCID. The goal of the present SBIR Phase I projectis to advance the development of extended-release (ER) subcutaneous injection formulation for theadministration of our novel peptide therapy, PNA5, for VCID. These novel peptide formulations are designedto act on Mas receptors (MasR) within the brain vascular endothelium, neuronal cells and microglia to decreasebrain reactive oxygen (ROS) production and neuroinflammation. We have begun to translate these preclinicalfindings into novel peptide therapeutics to treat cognitive impairment in patients with heart disease who are atrisk for ADRD or VCID. With support from NIA, we are currently completing our formal IND enabling toxicologystudies required to advance PNA5 to human clinical trials for VCID and expect to submit our IND application byQ1 2023. Our current planned treatment protocol for VCID patients is once a day, subcutaneous 100 microg/kginjection using a standard needle and syringe for 85 days. However, to increase patient compliance as well asaccelerate commercialization we are currently investigating new formulations that are more patient friendly andrequire fewer injections. We will take advantage of Drug Delivery Experts LLC (now Pace Labs) extensiveexperience in the formulation of poly(lactic-co-glycolic acid) (PLGA) sterile injectable in-situ gel formulations andmanufacturing expertise to complete the 2 principal objectives of this project.Objective 1: Complete formulation development and scale up batch manufacturing of our extended-release in-situ gel injection formulation of PNA5.Objective 2. Complete in vivo PK studies of the extended-release injection formulations and compare tostandard saline formulations of PNA5.Following successful completion of these feasibility studies, in Phase II we will conduct extensive PD/PKstudies of the PNA5-PLGA formulation in our VCID animal model to establish the cognitive protective and anti-inflammatory effects of PNA5-PLGA and begin formal toxicology IND enabling studies.
Public Health Relevance Statement: Resource Data Sharing Plan
Plan for Intellectual Property and Sharing of Research Resources
Intellectual property and data generated under this project will be administered in accordance with NIH
policies, including the NIH Data Sharing Policy and Implementation Guidance of March 5, 2003.
Ownership of sole or joint inventions developed under the project will be owned by the institution(s) employing
the inventor(s). Inventors shall be determined by U.S. Patent law, Title 35 SC. Participating
investigators/institutions will disclose any inventions developed under the project and such inventions will be
reported and managed as provided by NIH policies.
Sole inventions will be administered by the institution employing the inventor. Joint inventions shall be
administered based on mutual consultation between the parties. Similar procedures will be followed for
copyrights.
Materials generated under the project will be disseminated in accordance with Participating institutional and
NIH policies. Depending on such policies, materials may be transferred to others under the terms of a material
transfer agreement.
Access to databases and associated software tools generated under the project will be available for
educational, research and non-profit purposes. Such access will be provided using web-based applications, as
appropriate.
Publication of data shall occur during the project, if appropriate, or at the end of the project, consistent with
normal scientific practices. Research data which documents, supports and validates research findings will be
made available after the main findings from the final research data set have been accepted for
publication. Such research data will be redacted to prevent the disclosure of personal identifiers.
Project Terms: | 