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Integrin-targeted siRNA delivery for therapeutic gene silencing in blood cancers

Award Number: R01CA139444
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/10/2010
PERIOD OF PERFORMANCE END DATE: 12/31/2014

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Integrin-targeted siRNA delivery for therapeutic gene silencing in blood cancers - DESCRIPTION (provided by applicant): Activation of RNA interference (RNAi), a sequence-specific gene silencing mechanism, by synthetic small interfering (si)RNAs holds great promise as a novel therapeutic approach. siRNAs now represent the most promising type of RNAi-based therapeutics currently advancing in preclinical and clinical trials. Specifically, using siRNAs to suppress gene expression of specific molecule in hematologic cells would not only facilitates our understanding of the mechanism of disease, but could also help us develop RNAi-based and mechanism- oriented medicine to treat incurable blood cancers (e.g., multiple myeloma). However, blood cancers are among the most difficult targets for siRNA delivery, as they are resistant to conventional transfection reagents, and disperse in the body, making it hard to successfully localize or passively deliver via systemic administration. This is further compounded by the lack of systemically applicable technologies for selectively targeting siRNAs to blood cancers. In order to realize RNAi-based cancer treatment, the development of robust siRNA delivery technologies is imperative. Indeed, they must enable effective and specific gene silencing in target cells while mitigating off-target effects. We have addressed this specific problem by developing integrin-targeted stabilized nanoparticles (I-tsNP): nano-sized stabilized neutral liposomes that encapsulate siRNAs and that are selectively directed to blood cancer cells via surface-attached monoclonal antibodies (mAbs) to leukocyte integrins (e.g., alphaLbeta2 [LFA-1] and beta7 integrins). We have demonstrated in our preliminary data that siRNA delivery with I-tsNP induced potent gene silencing selectively in hematologic cells in vivo. We now intend to further validate and enhance the ability of I-tsNP to deliver siRNAs to blood cancers for in vivo applications. Aim 1 is to test the hypothesis that I-tsNP serves as the optimal siRNA delivery technology to hematologic cells, thereby facilitating the validation of drug targets in vivo. To establish the groundwork for performing siRNA-based drug target validation in mice, we will define the in vivo delivery and safety profiles of I-tsNP that targets hematologic cell-specific integrins. Aim 2 is to validate the hypothesis that siRNA delivery by I-tsNP induces therapeutic gene silencing in blood cancers using multiple myeloma (MM) as a model. Encapsulating, into the nanoparticles, the siRNAs to established MM drug targets (e.g., AKT, HSP90, or HDAC6), we will validate I-tsNP in a highly clinically relevant xenograft model bearing human MM cell in human bone marrow microenvironment (i.e., SCID-hu MM model). Aim 3 is to substantiate the hypothesis that high-affinity conformation of the integrin LFA-1 can be used for selectively targeting siRNAs to MM cells. Using mAb AL-57 that preferentially binds to the high-affinity LFA-1, we will study the ability of I-tsNP to selectively deliver siRNAs in vivo to MM cells that express aberrantly activated LFA-1. I-tsNP, as proposed in these contexts, should help establish a siRNA delivery platform technology that will realize RNAi-based medicine for blood cancers.


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: 2014 ( Subtotal = $390,943 )
2014	2014	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	10	7/2/2014	NON-COMPETING CONTINUATION	$390,943
														Subtotal = $390,943

Issue Date FY: 2013 ( Subtotal = $378,852 )
2013	2013	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	002	9	7/3/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$197,487
2013	2013	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	9	1/30/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$181,365
2013	2012	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	001	8	1/30/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $378,852

Issue Date FY: 2012 ( Subtotal = $439,110 )
2012	2012	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	8	5/2/2012	NON-COMPETING CONTINUATION	$439,110
														Subtotal = $439,110

Issue Date FY: 2011 ( Subtotal = $439,110 )
2011	2011	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	001	7	5/13/2011	NON-COMPETING CONTINUATION	$31,688
2011	2011	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	7	12/8/2010	NON-COMPETING CONTINUATION	$407,422
														Subtotal = $439,110

Issue Date FY: 2010 ( Subtotal = $452,691 )
2010	2010	IMMUNE DISEASE INSTITUTE INC	800 HUNTINGTON AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Treatment Research	000	6	3/10/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$452,691
														Subtotal = $452,691

Grand Total All Awards = $2,100,706

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Integrin-targeted siRNA delivery for therapeutic gene silencing in blood cancers

Award Number: R01CA139444

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/10/2010

PERIOD OF PERFORMANCE END DATE: 12/31/2014

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