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Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2010.2.4.4-1 | Award Amount: 4.35M | Year: 2011

Acute intermittent porphyria (AIP) is a rare genetic disease in which mutations in the porphobilinogen deaminase (PBGD) gene produce insufficient activity of a protein necessary for heme synthesis. This leads to an accumulation of toxic intermediates resulting in a wide variety of problems including acute, severe abdominal pains, psychiatric and neurological disorders, and muscular weakness. Acute porphyric attacks can be life-threatening and the long-term consequences include irreversible nerve damage, liver cancer and kidney failure. AIP affects 1/10,000 people in the EU and the therapies currently available do not prevent the symptoms or consequences of acute porphyric attacks. The only curative therapy is liver transplantation and thus, new curative options are clearly needed. In 2009, the European Medicines Agency granted Orphan Drug Designation to AAV5-AAT-PBGD for the treatment of AIP. AAV is a replication-incompetent virus that has been modified to deliver genes or genetic material into human tissues or cells. AAV5-AAT-PBGD acts by delivering the PBGD expression cassette directly into hepatocytes. In heterozygous AIP patient that show 50% of the normal activity the additional PBGD activity will be sufficient to prevent the accumulation of toxic metabolites and thus, to prevent porphyric attacks. the aim of this project is the clinical development of the orphan drug AAV-AAT-PBGD for use to treat AIP. The project will be performed in three different phases. In the first phase, we will develop a GMP-compliant process to produce sufficient AAV5-AAT-PBGD for clinical trials, and we will constitute the largest possible cohorts to improve the follow-up of patients and determine the clinical criteria to select patients for gene therapy. In the second phase, the safety and efficacy of AAV5-AAT-PBGD will be explored in a dose escalation clinical phase I/II trial.


Merriam-Webster's online dictionary defines purgatory as "an intermediate state after death for expiatory purification" or more specifically as "a place or state of punishment wherein according to Roman Catholic doctrine the souls of those who die in God's grace may make satisfaction for past sins and so become fit for heaven." Alternatively, it is defined as "a place or state of temporary suffering or misery." Either way, purgatory is a place where you are stuck, and you don't want to be stuck there. It is in this context that the term genetic purgatory is introduced. Genetic purgatory is a place where the genetic test-ordering physician and patients and their families are stuck when a variant of uncertain/unknown significance (VUS) has been elucidated. It is in this dark place where suffering and misery are occurring because of unenlightened handling of a VUS, which includes using the VUS for predictive genetic testing and making radical treatment recommendations based on the presence or absence of a so-called maybe mutation. Before one can escape from this miserable place, one must first recognize that one is stuck there. Hence, the purpose of this review article is to fully expose the VUS issue as it relates to the cardiac channelopathies and make the cardiologists/geneticists/genetic counselors who order such genetic tests believers in genetic purgatory. Only then can one meaningfully attempt to get out of that place and seek to promote a VUS to disease-causative mutation status or demote it to an utterly innocuous and irrelevant variant. © 2015 Heart Rhythm Society.


Hall I.P.,Molecular Therapeutics
European Respiratory Review | Year: 2013

It is well recognised that genetic factors play a major role in the development of respiratory diseases such as asthma and chronic obstructive pulmonary disease. However, whilst extensive data exist on diseases caused primarily by single gene defects, such as α1-antitrypsin deficiency, the genetic factors responsible for the development of complex disease are only now being defined. Once the gene(s) responsible for the heritable element of disease risk are known, the next step is to identify the mechanisms underlying the pathophysiological effects of the causal mutations in these genes. This process can be time consuming, but allows a full understanding of the mechanisms underlying disease development to be obtained. This knowledge can then potentially be used to stratify patient groups within (or even across) disease boundaries and then to target therapy more effectively. © ERS 2013.


Ambudkar I.S.,Molecular Therapeutics
Current Medicinal Chemistry | Year: 2012

The secretion of fluid, electrolytes, and protein by exocrine gland acinar cells is a vectorial process that requires the coordinated regulation of multiple channel and transporter proteins, signaling components, as well as mechanisms involved in vesicular fusion and water transport. Most critical in this is the regulation of cytosolic free [Ca2+] ([Ca 2+]i) in response to neurotransmitter stimulation. Control of [Ca2+]i increase in specific regions of the cell is the main determinant of fluid and electrolyte secretion in salivary gland acinar cells as it regulates several major ion flux mechanisms as well as the water channel that are required for this process. Polarized [Ca2+] i signals are also essential for protein secretion in pancreatic acinar cells. Thus, the mechanisms that generate and modulate these compartmentalized [Ca2+]i signals are central to the regulation of exocrine secretion. These mechanisms include membrane receptors for neurotransmitters, intracellular Ca2+ release channels, Ca 2+ entry channels, as well Ca2+ as pumps and mitochondria. The spatial arrangement of proteins involved in Ca2+ signaling is of primary significance in the generation of specific compartmentalized [Ca 2+]i signals. Within these domains, both local and global [Ca2+]i changes are tightly controlled. Control of secretion is also dependent on the targeting of ion channels and transporters to specific domains in the cell where their regulation by [Ca2+] i signals is facilitated. Together, the polarized localization of Ca2+ signaling and secretory components drive vectorial secretion of fluid, electrolytes, and proteins in the exocrine salivary glands and pancreas. This review will discuss recent findings which have led to resolution of the molecular components underlying the spatio-temporal control of [Ca 2+]i signals in exocrine gland cells and their role in secretion. © 2012 Bentham Science Publishers.


Jones C.,Molecular Therapeutics | Baker S.J.,St Jude Childrens Research Hospital
Nature Reviews Cancer | Year: 2014

Diffuse high-grade gliomas (HGGs) of childhood are a devastating spectrum of disease with no effective cures. The two-year survival for paediatric HGG ranges from 30%, for tumours arising in the cerebral cortex, to less than 10% for diffuse intrinsic pontine gliomas (DIPGs), which arise in the brainstem. Recent genome-wide studies provided abundant evidence that unique selective pressures drive HGG in children compared to adults, identifying novel oncogenic mutations connecting tumorigenesis and chromatin regulation, as well as developmental signalling pathways. These new genetic findings give insights into disease pathogenesis and the challenges and opportunities for improving patient survival in these mostly incurable childhood brain tumours. © 2014 Macmillan Publishers Limited. All rights reserved.


McMurray C.T.,Lawrence Berkeley National Laboratory | McMurray C.T.,Molecular Therapeutics | McMurray C.T.,Mayo Medical School
Nature Reviews Genetics | Year: 2010

Trinucleotide expansion underlies several human diseases. Expansion occurs during multiple stages of human development in different cell types, and is sensitive to the gender of the parent who transmits the repeats. Repair and replication models for expansions have been described, but we do not know whether the pathway involved is the same under all conditions and for all repeat tract lengths, which differ among diseases. Currently, researchers rely on bacteria, yeast and mice to study expansion, but these models differ substantially from humans. We need now to connect the dots among human genetics, pathway biochemistry and the appropriate model systems to understand the mechanism of expansion as it occurs in human disease. © 2010 Macmillan Publishers Limited. All rights reserved.


Mathelier A.,Molecular Therapeutics | Shi W.,Molecular Therapeutics | Wasserman W.W.,Molecular Therapeutics
Trends in Genetics | Year: 2015

It has long been appreciated that variations in regulatory regions of genes can impact gene expression. With the advent of whole-genome sequencing (WGS), it has become possible to begin cataloging these noncoding variants. Evidence continues to accumulate linking clinical cases with cis-regulatory element disruption in a wide range of diseases. Identifying variants is becoming routine, but assessing their impact on regulation remains challenging. Bioinformatics approaches that identify variations functionally altering transcription factor (TF) binding are increasingly important for meeting this challenge. We present the current state of computational tools and resources for identifying the genomic regulatory components (cis-regulatory regions and TF binding sites, TFBSs) controlling gene transcriptional regulation. We review how such approaches can be used to interpret the potential disease causality of point mutations and small insertions or deletions. We hope this will motivate further the development of methods enabling the identification of etiological cis-regulatory variations. © 2015 Elsevier Ltd.


Kenakin T.P.,Glaxosmithkline | Miller L.J.,Molecular Therapeutics
Pharmacological Reviews | Year: 2010

It is useful to consider seven transmembrane receptors (7TMRs) as disordered proteins able to allosterically respond to a number of binding partners. Considering 7TMRs as allosteric systems, affinity and efficacy can be thought of in terms of energy flow between a modulator, conduit (the receptor protein), and a number of guests. These guests can be other molecules, receptors, membrane-bound proteins, or signaling proteins in the cytosol. These vectorial flows of energy can yield standard canonical guest allostery (allosteric modification of drug effect), effects along the plane of the cell membrane (receptor oligomerization), or effects directed into the cytosol (differential signaling as functional selectivity). This review discusses these apparently diverse pharmacological effects in terms of molecular dynamics and protein ensemble theory, which tends to unify 7TMR behavior toward cells. Special consideration will be given to functional selectivity (biased agonism and biased antagonism) in terms of mechanism of action and potential therapeutic application. The explosion of technology that has enabled observation of diverse 7TMR behavior has also shown how drugs can have multiple (pluridimensional) efficacies and how this can cause paradoxical drug classification and nomenclatures. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.


Kenny P.J.,Molecular Therapeutics | Kenny P.J.,Scripps Research Institute
Nature Reviews Neuroscience | Year: 2011

The hedonic properties of food can stimulate feeding behaviour even when energy requirements have been met, contributing to weight gain and obesity. Similarly, the hedonic effects of drugs of abuse can motivate their excessive intake, culminating in addiction. Common brain substrates regulate the hedonic properties of palatable food and addictive drugs, and recent reports suggest that excessive consumption of food or drugs of abuse induces similar neuroadaptive responses in brain reward circuitries. Here, we review evidence suggesting that obesity and drug addiction may share common molecular, cellular and systems-level mechanisms. © 2011 Macmillan Publishers Limited. All rights reserved.


Jonkman S.,Molecular Therapeutics | Kenny P.J.,Molecular Therapeutics
Neuropsychopharmacology | Year: 2013

The rewarding properties of cocaine play a key role in establishing and maintaining the drug-taking habit. However, as exposure to cocaine increases, drug use can transition from controlled to compulsive. Importantly, very little is known about the neurobiological mechanisms that control this switch in drug use that defines addiction. MicroRNAs (miRNAs) are small non-protein coding RNA transcripts that can regulate the expression of messenger RNAs that code for proteins. Because of their highly pleiotropic nature, each miRNA has the potential to regulate hundreds or even thousands of protein-coding RNA transcripts. This property of miRNAs has generated considerable interest in their potential involvement in complex psychiatric disorders such as addiction, as each miRNA could potentially influence the many different molecular and cellular adaptations that arise in response to drug use that are hypothesized to drive the emergence of addiction. Here, we review recent evidence supporting a key role for miRNAs in the ventral striatum in regulating the rewarding and reinforcing properties of cocaine in animals with limited exposure to the drug. Moreover, we discuss evidence suggesting that miRNAs in the dorsal striatum control the escalation of drug intake in rats with extended cocaine access. These findings highlight the central role for miRNAs in drug-induced neuroplasticity in brain reward systems that drive the emergence of compulsive-like drug use in animals, and suggest that a better understanding of how miRNAs control drug intake will provide new insights into the neurobiology of drug addiction. © 2013 American College of Neuropsychopharmacology. All rights reserved.

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