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Crenshaw D.G.,Duke University | Gottschalk W.K.,Duke University | Lutz M.W.,Duke University | Grossman I.,IsraGene Ltd. | And 7 more authors.
Clinical Pharmacology and Therapeutics | Year: 2013

Curing Alzheimer's disease (AD) remains an elusive goal; indeed, it may even prove to be impossible, given the nature of the disease. Although modulating disease progression is an attractive target and will alleviate the burden of the most severe stages, this strategy will not reduce the prevalence of the disease itself. Preventing or (as described in this article) delaying the onset of cognitive impairment and AD will provide the greatest benefit to individuals and society by pushing the onset of disease into the later years of life. Because of the high variability in the age of onset of the disease, AD prevention studies that do not stratify participants by age-dependent disease risk will be operationally challenging, being large in size and of long duration. We present a composite genetic biomarker to stratify disease risk so as to facilitate clinical studies in high-risk populations. In addition, we discuss the rationale for the use of pioglitazone to delay the onset of AD in individuals at high risk. © 2013 American Society for Clinical Pharmacology and Therapeutics.


Patent
Zinfandel Pharmaceuticals Inc. and Takeda Pharmaceutical | Date: 2016-12-21

Provided herein are drug products with low dose pioglitazone for use in the treatment (e.g., delay of onset) of cognitive impairment of the Alzheimers type. Methods of manufacture thereof are also provided. Further provided are methods of treatment for Alzheimers disease including administering a drug product with low dose pioglitazone. The methods may include determining whether the subject is at risk of developing Alzheimers disease based upon the subjects age and TOMM40 523 genotype.


Patent
Takeda Pharmaceutical and Zinfandel Pharmaceuticals Inc. | Date: 2015-06-15

Provided herein are drug products with low dose pioglitazone for use in the treatment (e.g., delay of onset) of cognitive impairment of the Alzheimers type. Methods of manufacture thereof are also provided. Further provided are methods of treatment for Alzheimers disease including administering a drug product with low dose pioglitazone. The methods may include determining whether the subject is at risk of developing Alzheimers disease based upon the subjects age and TOMM40 523 genotype.


PubMed | Pennsylvania State University, Zinfandel Pharmaceuticals Inc. and Takeda Development Center Americas Inc.
Type: Journal Article | Journal: PloS one | Year: 2015

Pioglitazone (PIO) is a peroxisome proliferator-activated receptor- (PPAR) agonist in clinical use for treatment of type 2 diabetes (T2DM). Accumulating evidence suggests PPAR agonists may be useful for treating or delaying the onset of Alzheimers disease (AD), possibly via actions on mitochondria, and that dose strengths lower than those clinically used for T2DM may be efficacious. Our major objective was to determine if low doses of pioglitazone, administered orally, impacted brain activity. We measured blood-oxygenation-level dependent (BOLD) low-frequency fluctuations in conscious rats to map changes in brain resting-state functional connectivity due to daily, oral dosing with low-dose PIO. The connectivity in two neural circuits exhibited significant changes compared with vehicle after two days of treatment with PIO at 0.08 mg/kg/day. After 7 days of treatment with a range of PIO dose-strengths, connections between 17 pairs of brain regions were significantly affected. Functional connectivity with the CA1 region of the hippocampus, a region that is involved in memory and is affected early in the progression of AD, was specifically investigated in a seed-based analysis. This approach revealed that the spatial pattern of CA1 connectivity was consistent among all dose groups at baseline, prior to treatment with PIO, and in the control group imaged on day 7. Compared to baseline and controls, increased connectivity to CA1 was observed regionally in the hypothalamus and ventral thalamus in all PIO-treated groups, but was least pronounced in the group treated with the highest dose of PIO. These data support our hypothesis that PIO modulates neuronal and/or cerebrovascular function at dose strengths significantly lower than those used to treat T2DM and therefore may be a useful therapy for neurodegenerative diseases including AD.


PubMed | CA Technologies, Zinfandel Pharmaceuticals Inc, State University of New York at Stony Brook, Duke University and Cabernet Pharmaceuticals Inc.
Type: Journal Article | Journal: Alzheimer's & dementia : the journal of the Alzheimer's Association | Year: 2014

Several studies have demonstrated a lower apolipoprotein E4 (APOE 4) allele frequency in African-Americans, but yet an increased age-related prevalence of AD. An algorithm for prevention clinical trials incorporating TOMM40523 (Translocase of Outer Mitochondria Membrane) and APOE depends on accurate TOMM40523-APOE haplotypes.We have compared the APOE and TOMM40523 phased haplotype frequencies of a 9.5 kb TOMM40/APOE genomic region in West African, Caucasian, and African-American cohorts.African-American haplotype frequency scans of poly-T lengths connected in phase with either APOE 4 or APOE 3 differ from both West Africans and Caucasians and represent admixture of several distinct West African and Caucasian haplotypes. A new West African TOMM40523 haplotype, with APOE 4 connected to a short TOMM40523 allele, is observed in African-Americans but not Caucasians.These data have therapeutic implications for the age of onset risk algorithm estimates and the design of a prevention trial for African-Americans or other mixed ethnic populations.


Lutz M.W.,Duke University | Crenshaw D.,Zinfandel Pharmaceuticals Inc. | Welsh-Bohmer K.A.,Duke University | Burns D.K.,Zinfandel Pharmaceuticals Inc. | And 2 more authors.
Current Neurology and Neuroscience Reports | Year: 2016

Clinical trials for Alzheimer’s disease are now focusing on the earliest stages of the disease with the goal of delaying dementia onset. There is great utility in using genetic variants to identify individuals at high age-dependent risk when the goal is to begin treatment before the development of any cognitive symptoms. Genetic variants identified through large-scale genome-wide association studies have not substantially improved the accuracy provided by APOE genotype to identify people at high risk of late-onset Alzheimer’s disease (LOAD). We describe novel approaches, focused on molecular phylogenetics, to finding genetic variants that predict age at LOAD onset with sufficient accuracy and precision to be useful. We highlight the discovery of a polymorphism in TOMM40 that, in addition to APOE, may improve risk prediction and review how TOMM40 genetic variants may impact the develop of LOAD independently from APOE. The analysis methods described in this review may be useful for other genetically complex human diseases. © 2016, Springer Science+Business Media New York.


Patent
Zinfandel Pharmaceuticals Inc. | Date: 2014-08-21

Provided herein are genetic variants associated with development of a condition of interest (e.g., Alzheimers disease). Methods of treatment with an active agent (e.g., with a particular active agent and/or at an earlier age) is also provided, upon detecting a genetic variant described herein. In some embodiments, the genetic variant is a deletion/insertion polymorphism (DIP) of the TOMM40 gene.


Patent
Zinfandel Pharmaceuticals Inc. | Date: 2014-07-16

Provided herein is a method for identifying a genetic variant that is associated with development of a condition of interest (e.g., Alzheimers disease), and genetic variants so identified. Methods of treatment with an active agent (e.g., with a particular active agent and/or at an earlier age) is also provided, upon detecting a genetic variant described herein. In some embodiments, the genetic variant is a deletion/insertion polymorphism (DIP) of the TOMM40 gene. Kits for determining if a subject is at increased risk of developing late onset Alzheimers disease is also provided. Kits for determining if a subject is responsive to treatment for a condition of interest with an active agent are further provided.


Provided herein is a method for identifying a genetic variant that is associated with development of a condition of interest (e.g., Alzheimers disease), and genetic variants so identified. Methods of treatment with an active agent (e.g., with a particular active agent and/or at an earlier age) is also provided, upon detecting a genetic variant described herein. In some embodiments, the genetic variant is a deletion/insertion polymorphism (DIP) of the TOMM40 gene. Kits for determining if a subject is at increased risk of developing late onset Alzheimers disease is also provided. Kits for determining if a subject is responsive to treatment for a condition of interest with an active agent are further provided..


PubMed | Duke University and Zinfandel Pharmaceuticals Inc.
Type: Journal Article | Journal: Current neurology and neuroscience reports | Year: 2016

Clinical trials for Alzheimers disease are now focusing on the earliest stages of the disease with the goal of delaying dementia onset. There is great utility in using genetic variants to identify individuals at high age-dependent risk when the goal is to begin treatment before the development of any cognitive symptoms. Genetic variants identified through large-scale genome-wide association studies have not substantially improved the accuracy provided by APOE genotype to identify people at high risk of late-onset Alzheimers disease (LOAD). We describe novel approaches, focused on molecular phylogenetics, to finding genetic variants that predict age at LOAD onset with sufficient accuracy and precision to be useful. We highlight the discovery of a polymorphism in TOMM40 that, in addition to APOE, may improve risk prediction and review how TOMM40 genetic variants may impact the develop of LOAD independently from APOE. The analysis methods described in this review may be useful for other genetically complex human diseases.

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