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Intranasal Nanodelivery of Oxytocin to Treat Morphine Addiction in HIV Patients by Gene Editing

Award Number: R03DA044877
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2017
PERIOD OF PERFORMANCE END DATE: 06/30/2020

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Intranasal Nanodelivery of Oxytocin to Treat Morphine Addiction in HIV Patients by Gene Editing - Intranasal Nanodelivery of Oxytocin to Treat Morphine Addiction in HIV Patients by Gene Editing Despite significant developments, treating drug addiction in HIV-1 infected subjects remain as a challenge. Morphine has been shown to exaggerate HIV-induced risk in patients, which deteriorates the brain function and leads to dysregulation of endocrine-metabolic system. This dysregulation might lead to disturbances in the hypothalamic-pituitary-thyroid (HPT) axis, which may indirectly effect the production of Oxytocin (OXT) (neurohypophyseal nona-neuropeptide synthesized in the brain released at the posterior pituitary). Despite the extensive literature on OXT's role in addiction therapy, there are no direct studies available investigating the effects of or on OXT during concurrent Morphine addiction and HIV-1 infection. Also, it has previously been shown that exogenous OXT delivery inhibits the development of acute and chronic morphine tolerance and attenuate the various symptoms of morphine withdrawal in dose dependent manner. OXT may act as a neuromodulator on dopaminergic neurotransmission in limbic-basal forebrain structures to regulate adaptive CNS processes leading to drug addiction. Repeated morphine ingestion will upregulate mu (µ)-opioid receptor and lead to inhibition of OXT production, which may eventually cause the development of tolerance and physical dependence. Though the OXT has significant therapeutic advantages there are insufficient levels of OXT in compromised diseased state and exogenous OXT expressing source becomes an important need. Exogenous OXT delivery becomes complicated pertaining to factors like plasma half-life and poor oral bioavailability, and limited penetrance of the blood-brain barrier (BBB) due to their large size and hydrophilic nature. Therefore, delivery of a stable and efficacious active gene encoding protein directly into the brain that would reverse the effects of morphine addiction may serve as an effective approach against HIV-1 infected drug abusing subjects. Considering these preclinical limitations related to its delivery and to address this issue, we have developed a novel polyplex nanoformulation of OXT encoding CRISPR activation plasmid by lab developed nontoxic derivative of PEI [P(SiDAAr)5P3] using novel simultaneous spray (SS) technique. Our preliminary results show that SS prepared pGFP polyplex using P(SiDAAr)5P3 (non-viral transfecting agent) could form uniform, small, stable, non-toxic polyplex and achieved significant higher transfection efficiency compared to commercially available jetPEI. To translate this novel technology as anti-addiction therapeutics in HIV-1 treatment paradigm and to achieve the goals, we propose to study the effect of spraying parameters, important formulation aspects and efficacy evaluation of SS-prepared OXT- formulation against Morphine ± HIV-1 Tat challenge using primary human neurons (Aim-1). generate i nhalable aerosol formulation of OXT- P(SiDAAr)5P3 polyplex Further as a proof of concept, we propose to P(SiDAAr)5P3 polyplex and evaluate intranasal CNS delivery in OXTtm1Wsy/OXTtm1Wsy (OXT deficient- OXTDef) mice exposed to Morphine ± HIV-1 Tat (Aim-2). Data generated using this grant will be used for future R01 grant proposal.


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: 2020 ( Subtotal = -$376 )
2020	2018	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Drug Use and Addiction Research Programs	000	3	9/5/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$376
														Subtotal = -$376

Issue Date FY: 2019 ( Subtotal = $6,500 )
2019	2018	FLORIDA INTERNATIONAL UNIVERSITY	11200 S W 8TH ST MARC 430	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	000	2	1/7/2019	NON-COMPETING CONTINUATION	-$146,500
2019	2018	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST	LUBBOCK	TX	79430	LUBBOCK	USA	Drug Use and Addiction Research Programs	001	3	1/7/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$153,000
2019	2018	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Drug Use and Addiction Research Programs	003	3	7/10/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$69,783
2019	2017	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	002	1	7/10/2019	NEW	-$69,783
														Subtotal = $6,500

Issue Date FY: 2018 ( Subtotal = $146,500 )
2018	2018	FLORIDA INTERNATIONAL UNIVERSITY	11200 S W 8TH ST MARC 430	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	000	2	6/6/2018	NON-COMPETING CONTINUATION	$146,500
														Subtotal = $146,500

Issue Date FY: 2017 ( Subtotal = $146,500 )
2017	2017	FLORIDA INTERNATIONAL UNIVERSITY	11200 S W 8TH ST MARC 430	MIAMI	FL	33199	MIAMI-DADE	USA	Drug Use and Addiction Research Programs	000	1	6/30/2017	NEW	$146,500
														Subtotal = $146,500

Grand Total All Awards = $299,124

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Intranasal Nanodelivery of Oxytocin to Treat Morphine Addiction in HIV Patients by Gene Editing

Award Number: R03DA044877

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2017

PERIOD OF PERFORMANCE END DATE: 06/30/2020

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