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Treatment of Duchenne Muscular Dystrophy with Cas9 Protein Complexed to Gold Nanoparticles

Award Number: R01EB023776
ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2017
PERIOD OF PERFORMANCE END DATE: 05/31/2022

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Treatment of Duchenne Muscular Dystrophy with Cas9 Protein Complexed to Gold Nanoparticles - Abstract Duchenne muscular dystrophy (DMD) is a genetic disease caused by mutations in the dystrophin gene and causes thousands of deaths each year. There are no effective treatments for DMD and new DMD therapeutics are urgently needed. Cas9 based therapeutics have the potential to revolutionize the treatment of DMD, because they can correct dystrophin mutations, via homology directed DNA repair. However, developing Cas9 based therapeutics for DMD has been challenging because it requires simultaneously delivering Cas9 protein, guide RNA, and donor DNA in vivo and delivery vehicles have not been developed that can accomplish this. The central objective of this proposal is to develop a new family of nanoparticle delivery vehicles, termed CRISPR-Nanoparticles, which are designed to treat DMD by delivering Cas9 protein, guide RNA and donor DNA in vivo. CRISPR-Gold is our first generation CRISPR-Nanoparticle and is composed of gold nanoparticles complexed with Cas9 RNP, donor DNA and the endosomal disruptive polymer PASp(DET). We have been able to demonstrate that CRISPR-Gold, can correct 5% of the dystrophin mutations (via HDR) in muscle fibers after a direct injection in mdx mice, and thus has tremendous potential as a treatment for DMD. A successful DMD therapeutic needs to be able to correct 20% of the dystrophin mutations in muscle tissue, and the experiments in this proposal focus on developing 2nd and 3rd generation CRISPR-Nanoparticles, which can generate a 20% HDR rate in muscle tissue. In particular, the 2nd and 3rd generation CRISPR- Nanoparticles address the key factors preventing CRISPR-Gold from generating a 20% HDR rate in a clinical setting, which are (1) its lack of biodegradability, (2) its toxicity, and (3) the lack of cell division in muscle tissue. The central hypothesis of this proposal is that: Delivery vehicles that complex Cas9 protein, guide RNA, donor DNA and endosomal disruptive polymers will be able to efficiently induce HDR and treat DMD. The central objective of this proposal will be accomplished by completing the following Specific Aims. Specific Aim 1: Develop biodegradable CRISPR-Nanoparticles that can correct dystrophin mutations Specific Aim 2: Develop biocompatible CRISPR-Nanoparticles that can correct dystrophin mutations Specific Aim 3: Enhance the HDR efficiency of CRISPR-Nanoparticles with FDA approved stimulating agents At the conclusion of this proposal we will have identified a CRISPR-Nanoparticle formulation that can efficiently correct dystrophin mutations in vivo and has the biocompatibility needed for clinical translation. The experiments in this proposal are innovative because CRISPR-Gold is the first example of a delivery vehicle that can simultaneously deliver RNA, DNA and protein in vivo and induce HDR. The experiments in this proposal are significant because they will lead to the development of a new therapeutic for DMD (and other genetic diseases) that has the HDR efficiency and biocompatibility needed to enter into clinical trials.


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: 2023 ( Subtotal = -$211 )
2023	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	4	11/21/2022	NON-COMPETING CONTINUATION	-$211
														Subtotal = -$211

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	4	8/27/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $353,250 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	4	7/9/2020	NON-COMPETING CONTINUATION	$353,250
														Subtotal = $353,250

Issue Date FY: 2019 ( Subtotal = $353,250 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	3	5/30/2019	NON-COMPETING CONTINUATION	$353,250
														Subtotal = $353,250

Issue Date FY: 2018 ( Subtotal = $353,250 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	2	5/22/2018	NON-COMPETING CONTINUATION	$353,250
														Subtotal = $353,250

Issue Date FY: 2017 ( Subtotal = $353,250 )
2017	2017	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	1	8/15/2017	NEW	$353,250
														Subtotal = $353,250

Grand Total All Awards = $1,412,789

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Treatment of Duchenne Muscular Dystrophy with Cas9 Protein Complexed to Gold Nanoparticles

Award Number: R01EB023776

ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/15/2017

PERIOD OF PERFORMANCE END DATE: 05/31/2022

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