# Ex Vivo Nanoparticle Drug Delivery Targeted to Human Renal Allograft Endothelium

> **NIH NIH U01** · YALE UNIVERSITY · 2020 · $418,750

## Abstract

A significant proportion of patients with renal failure who would benefit from kidney transplantation are highly
pre-sensitized, i.e. they have high titers of pre-formed circulating antibodies (Abs) reactive with 80% or more of
non-self allelic forms of class I and/or class II HLA antigens called panel reactive Abs (PRA). Upon
transplantation, host PRA will bind to graft HLA antigens that are highly expressed on graft endothelial cells
(ECs) where they activate host human complement resulting in deposition of membrane attack complex (MAC)
on the ECs. Human MAC does not lyse human ECs, but instead alters them to express gene products that
promote inflammation. The inflammatory milieu favors activation of adaptive immune effectors at the expense
of protective immunoregulation. Consequently, if transplanted, patients with high titer PRA have increased
episodes of acute and chronic rejection resulting in more graft failure and graft loss. Current therapeutic
approaches include plasmapheresis to reduce the titer of circulating PRA, targeted elimination of Ab-producing
cells and/or administration of high doses of intravenous gamma globulin to reduce inflammation, but PRA titers
return and these interventions have had only limited impact on outcomes. We propose a novel strategy to
complement these approaches, namely to reduce the response of graft ECs to PRA/MAC by reducing
expression of HLA antigen targets and/or by inhibiting PRA/MAC signaling in ECs. The latter approach is
based upon our elucidation of the relevant signaling pathways. To accomplish this, we will develop safe,
polymeric nanoparticles (NPs) that are targeted towards graft ECs by means of conjugated anti-EC Abs and
use these NPs to deliver siRNAs or small molecule therapeutics (“drugs”) during a period of ex vivo
normothermic perfusion (EVNP), an approach that is being applied to improve energy stores in kidneys and
other organs from deceased donors prior to transplantation. The NPs, which will be bound to and internalized
by the graft ECs, will then serve as a depot for sustained release of the therapeutic agent for a period sufficient
to allow graft accommodation and/or host immunoregulation to develop. In Specific Aim 1, we will use human
EC cultures and human artery segments interposed into the aortae of immunodeficient mice to identify the
optimal siRNAs or drugs that can protect ECs from PRA. Our initial target will be prevention of Akt activation, a
key step in PRA/MAC signaling. In Specific Aim 2, we will identify optimal Abs for targeting renal human ECs
and use these to identify conditions for efficient pan-EC delivery in human kidneys unsuitable for clinical
transplantation that are subjected to EVNP by our collaborators at the University of Cambridge. (U01 support
will be used only for experiments and analyses conducted at Yale; the costs of experimental EVNP will be
provided by our Cambridge colleagues who are supported by a grant from the UK National Institute for Health
R...

## Key facts

- **NIH application ID:** 9962282
- **Project number:** 5U01AI132895-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** JORDAN S POBER
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $418,750
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962282

## Citation

> US National Institutes of Health, RePORTER application 9962282, Ex Vivo Nanoparticle Drug Delivery Targeted to Human Renal Allograft Endothelium (5U01AI132895-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9962282. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*