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Intraganglionic Analgesic Adeno-Associated Virus (AAV) Gene Vector Optimization in Large Animals

Award Number: R01NS100725
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/14/2019
PERIOD OF PERFORMANCE END DATE: 07/31/2023

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Intraganglionic Analgesic Adeno-Associated Virus (AAV) Gene Vector Optimization in Large Animals - Adeno-Associated Virus (AAV) gene therapy has the potential—as yet unrealized—to provide targeted anal- gesic agent delivery in pain patients, if optimized vectors can achieve a key objective in large animals: efficient and anatomically selective gene delivery to the neurons of a dorsal root ganglion (DRG). Such gene targeting could turn even opioids (gene-encoded) into a safe and non-addictive treatment of chronic locoregional pain. Pain is a national health problem affecting 116M Americans at a cost of $560B/year. Untargeted opioids used to treat pain such as oral oxycodone act on multiple neural structures other than the DRG causing side effects such as respiratory arrest (via the brainstem), hallucinations (via the cortex), and addiction (via the mesolimbic system). 18,893 Americans died from prescription opioids in 2014 and 1.9 million were addicted to them. Key technologies required for AAV gene therapy of pain already exist such as multiple therapeutic genes and a clear definition of a target cell population, DRG neurons. In fact, analgesic efficacy of DRG-directed AAV gene vectors has been thoroughly proven in rodent models. Astonishingly, however, large animal testing has not been reported for any analgesic gene vector, neither AAV nor any other vector type. Hypothesis: Anatomically selective delivery of AAV vectors encoding a known analgesic gene to select DRG can reverse pain-related behavior in a large animal model of a clinically common loco-regional pain syndrome. Aim 1. Optimize AAV vector design by high-throughput testing of strains in vivo in DRG of swine. A critical bottleneck in vector optimization is comparative testing of multiple strains in vivo. We will use the newly developed high throughput RNA-and-DNA “Barcode” sequencing methodology developed by the Co-I that allows concurrent quantification of transduction efficiency and transgene expression of up to hundreds of AAV strains in a single experiment to define the optimal vector characteristics for DRG neuron targeting. Aim 2. Develop Magnetic Resonance Imaging (MRI)-guided vector targeting to DRG in swine. MRI imaging of the swine spine showed superior demarcation of DRG compared with CT. MRI- mislocalization artifacts of needles used could be corrected in phantom models. We will develop MRI-guided AAV targeting of DRG by convection enhanced delivery while integrated toxicological endpoints into the aim. Aim 3. Test the analgesic efficacy of AAV in a model of chronic knee osteoarthritis (OA) pain in swine. Knee OA ranks amongst the two most common causes of chronic pain in humans. We established a model of chronic knee (“stifle”) OA in swine. We will use the model to test the analgesic efficacy and integrated toxicity endpoint of AAV expressing opioid genes in the DRG . Impact: Large animal gene transfer optimization and efficacy testing performed along with an assessment of toxicological endpoints will advance the concept of targeted analgesic AAV gene therapy of DRG to the point where a pre-IND discussion can be initiated and the additional investment in formal toxicology testing justified.


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: 2024 ( Subtotal = $0 )
2024	2021	INTERVENTIONAL ANALGESIX INC.	701 W MAIN ST	DURHAM	NC	27701	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $986,534 )
2021	2021	INTERVENTIONAL ANALGESIX INC	701 W MAIN ST STE 200	DURHAM	NC	27701	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	5	7/22/2021	NON-COMPETING CONTINUATION	$709,984
2021	2019	INTERVENTIONAL ANALGESIX INC	701 W MAIN ST STE 200	DURHAM	NC	27701	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	2/2/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$276,550
2021	2018	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/26/2021	NON-COMPETING CONTINUATION	$276,550
2021	2018	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/11/2021	NON-COMPETING CONTINUATION	$0
2021	2018	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	2/2/2021	NON-COMPETING CONTINUATION	-$276,550
														Subtotal = $986,534

Issue Date FY: 2020 ( Subtotal = $411,049 )
2020	2020	INTERVENTIONAL ANALGESIX INC	701 W MAIN ST STE 200	DURHAM	NC	27701	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	8/11/2020	NON-COMPETING CONTINUATION	$687,599
2020	2019	INTERVENTIONAL ANALGESIX INC	701 W MAIN ST STE 200	DURHAM	NC	27701	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/17/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2020	2018	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	2	9/9/2020	NON-COMPETING CONTINUATION	$94,290
2020	2018	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	7/20/2020	NON-COMPETING CONTINUATION	-$370,840
														Subtotal = $411,049

Issue Date FY: 2019 ( Subtotal = $489,103 )
2019	2019	INTERVENTIONAL ANALGESIX INC	701 W MAIN ST STE 200	DURHAM	NC	27701	DURHAM	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	9/19/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$489,103
2019	2018	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/12/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $489,103

Issue Date FY: 2018 ( Subtotal = $647,390 )
2018	2018	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/9/2018	NON-COMPETING CONTINUATION	$647,390
														Subtotal = $647,390

Issue Date FY: 2017 ( Subtotal = $666,076 )
2017	2017	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/10/2017	NEW	$666,076
														Subtotal = $666,076

Grand Total All Awards = $3,200,152

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Intraganglionic Analgesic Adeno-Associated Virus (AAV) Gene Vector Optimization in Large Animals

Award Number: R01NS100725

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/14/2019

PERIOD OF PERFORMANCE END DATE: 07/31/2023

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