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Clinical Development of Hydroxy-propyl beta cyclodextrin in Diabetic Kidney Disease
Summary Data Summary
Applicant Fornoni, Alessia
E-Mail Address afornoni@med.miami.edu
Project Title Clinical Development of Hydroxy-propyl beta cyclodextrin in Diabetic Kidney
Disease
CBU ID 13GHSU332
External SubContract ID 25732-45
Diabetic Complication Nephropathy
Funding Program Group Preclinical Testing Program [PT2013Q4]
Abstract Diabetic kidney disease (DKD) is the most common cause of end-stage kidney
disease in the US (1). Podocyte injury is an important feature of DKD in
patients with T1D or T2D (2-6), and podocytopenia is an independent predictor of
DKD progression. However, mechanisms of podocytopenia in DKD are poorly
understood.
In diabetes, cholesterol accumulation in adipocytes and hepatocytes contributes
to actin cytoskeleton remodeling (7), insulin resistance (8) and cell death
(9,10). Excessive cholesterol deposition has also been described in glomeruli of
rodent models of T1D and T2D (11-13) and can result from impaired cholesterol
efflux due to down-regulation of ATP-binding cassette transporter (ABCA1)
expression (11,13). Under normal conditions, ABCA1 mediates the efflux of
cholesterol and phospholipids to lipid-poor apolipoproteins (primarily apo-A1),
which then form nascent high-density lipoproteins (HDL). Our preliminary data in
glomerular transcripts from 70 patients with T2D and early DKD demonstrated
down-regulation of ABCA1 when compared with living transplant donors. In further
preliminary data, cholesterol accumulation and down-regulation of ABCA1 occurred
in podocytes exposed to the sera of patients with DKD or in response to
inflammatory stimuli related to DKD progression such as TNF-alpha and its
soluble receptors TNFR1 and TNFR2. Therefore, interventions that increase ABC
expression (such as liver X receptor agonist) may be beneficial in DKD but are
limited by the high incidence of adverse events (14) and by their intrinsic
lipogenic effects (15). One potential alternative to this limitation is to
utilize drugs that sequester cholesterol, such as cyclodextrins (16,17).
Cyclodextrins are cyclic oligosaccharides utilized in the food, drug delivery
and chemical industries. Hydroxy-propyl-beta cyclodextrin (CD) is also being
investigated for the treatment of Niemann-Pick disease type C1, a genetic
disorder characterized by lysosomal accumulation of cholesterol leading to
multiple organ dysfunction (18). Our preliminary data suggest that high dose CD
may protect podocyte function in DKD by reducing their cholesterol content, but
whether this is true for lower doses that are translatable to humans remains to
be established.
Based on these observations, we hypothesize that low dose CD protects podocytes
in DKD. To determine the effects of low dose subcutaneous CD on cholesterol
accumulation in podocytes, and its impact on podocyte injury, we will use animal
models of T2D and human podocytes cultured in the presence of the sera of
patients with T2D. We will also determine if low dose CD administered orally has
a similar effect on macroalbuminuria of CD administered subcutaneously since
oral administration of CD at 40 mg/kg/day is well tolerated and is as effective
as subcutaneous CD in reducing microalbuminuria in BTBR ob/ob mice.
Our proposal for the Preclinical Testing Program has high opportunity to
translate into successful drug development for the care of patients with DKD.
This will be highly feasible, as we have already reported that high dose CD
protects from DKD, we have obtained from Johnson & Johnson the CD drug master
file in preparation of our meeting with the FDA for the utilization of CD for
DKD, and CD is currently used by NIH in a Phase 1 trial for the treatment of
Niemann-Pick Disease Type C1.
Application PDF Application Research Plan
Status Contract Executed
Key Personnel
Salary Total Costs 26403
Supply Total Costs 12183
Equipment Total Costs 0
Travel/Other Total Costs 0
Direct Costs 38586
Indirect Costs Proposed 0
Total Costs Proposed 38586
Total Costs Approved 59229
Start Date 6/1/2014
End Date 5/31/2015
IFO Name Page, Susanne
IFO E-Mail Address 1320 South Dixie Highway, Gables One Tower, Suite 650, LC 2960
IACUC/IRB No. 11-004
IACUC/IRB Institution University of Miami - Medical Campus
Entity ID No. 1590624458A1
Report Request Date 7/31/2015
T1D NO
TypeCount
Invoices 6
Progress Reports 1
Data Submission


Invoices
UrlCBU IDExternal IDInstitutionDateDirectIndirectInvoiceBalancePDF
  View  13GHSU33225732-45University of Miami - Medical Campus7/27/2015$8,493.58-$8,493.58$3,911.98View PDF
  View  13GHSU33225732-45University of Miami - Medical Campus5/4/2015$7,098.36-$7,098.36$3,911.98View PDF
  View  13GHSU33225732-45University of Miami - Medical Campus4/2/2015$8,888.47-$8,888.47$3,911.98View PDF
  View  13GHSU33225732-45University of Miami - Medical Campus3/4/2015$3,426.19-$3,426.19$3,911.98View PDF
  View  13GHSU33225732-45University of Miami - Medical Campus2/3/2015$15,709.73-$15,709.73$3,911.98View PDF
  View  13GHSU33225732-45University of Miami - Medical Campus1/6/2015$11,700.69-$11,700.69$3,911.98View PDF
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