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Posts Tagged ‘Huntington’s disease’


TyrNovo’s Novel and Unique Compound, named NT219, selectively Inhibits the process of Aging and Neurodegenerative Diseases, without affecting Lifespan

Reporter: Aviva Lev-Ari, PhD, RN

A step toward development of drugs for diseases such as Alzheimer’s, Parkinson’s and Huntington’s

December 3, 2013

 

Jerusalem – A successful joint collaboration between researchers at The Hebrew university of Jerusalem and the startup company TyrNovo may lead to a potential treatment of brain diseases. The researchers found that TyrNovo’s novel and unique compound, named NT219, selectively inhibits the process of aging in order to protect the brain from neurodegenerative diseases, without affecting lifespan. This is a first and important step towards the development of future drugs for the treatment of various neurodegenerative maladies.
Human neurodegenerative diseases such as Alzheimer’s, Parkinson’s andHuntington’s diseases share two key features: they stem from toxic proteinaggregation and emerge late in life. The common temporal emergence pattern exhibited by these maladies proposes that the aging process negatively regulates protective mechanisms that prevent their manifestation early in life, exposing the elderly to disease. This idea has been the major focus of the work in the laboratory of Dr. Ehud Cohen of the Department of Biochemistry and Molecular Biology, at The Hebrew University of Jerusalem‘s Faculty of Medicine.
Dr. Cohen’s first breakthrough in this area occurred when he discovered, working with Dr. Ehud Cohenworms, that reducing the activity of the signaling mechanism conveyed through insulin and the growth hormone IGF1, a major aging regulating pathway, constituted a defense against the aggregation of the Aβ protein which is mechanistically-linked with Alzheimer’s disease. Later, he found that the inhibition of this signaling route also protected Alzheimer’s-model mice from behavioral impairments and pathological phenomena typical to the disease. In these studies, the path was reduced through genetic manipulation, a method not applicable in humans.
Dr. Hadas Reuveni, the CEO of TyrNovo, a startup company formed for the clinical development of NT219, and Professor Alexander Levitzki from the Department of Biological Chemistry at The Hebrew University, with their research teams, discovered a new set of compounds that inhibit the activity of the IGF1 signaling cascade in a unique and efficient mechanism, primarily for cancer treatment, and defined NT219 as the leading compound for further development.
Now, in a fruitful collaboration Dr. Cohen and Dr. Reuveni, together with Dr. Cohen’s associates Tayir El-Ami and Lorna Moll, have demonstrated that NT219 efficiently inhibits IGF1 signaling, in both worms and human cells. The inhibition of this signaling pathway by NT219 protected worms from toxic protein aggregation that in humans is associated with the development of Alzheimer’s or Huntington’s disease.
The discoveries achieved during this project, which was funded by the Rosetrees Trust of Britain, were published this week in the journal Aging Cell (“A novel inhibitor of the insulin/IGF signaling pathway protects from age-onset, neurodegeneration-linked proteotoxicity”). The findings strengthen the notion that the inhibition of the IGF1 signaling pathway has a therapeutic potential as a treatment for neurodegenerative disorders. They also point at NT219 as the first compound that provides protection from neurodegeneration-associated toxic protein aggregation through a selective manipulation of aging.
Cohen, Reuveni and Levitzki have filed a patent application that protects the use of NT219 as a treatment for neurodegenerative maladies through Yissum, the technology transfer company of The Hebrew University. Dr. Gil Pogozelich, chairman of Goldman Hirsh Partners Ltd., which holds the controlling interest in TyrNovo, says that he sees great importance in the cooperation on this project with The Hebrew University, and that TyrNovo represents a good example of how scientific and research initiatives can further health care together with economic benefits.
Recently, Dr. Cohen’s laboratory obtained an ethical approval to test the therapeutic efficiency of NT219 as a treatment in Alzheimer’s-model mice, hoping to develop a future treatment for hitherto incurable neurodegenerative disorders.
SOURCE

 

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Ribozymes and RNA Machines –  Work of Jennifer A. Doudna

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED 3/27/2014

New DNA-editing technology spawns bold UC initiative

http://newscenter.berkeley.edu/2014/03/18/new-dna-editing-technology-spawns-bold-uc-initiative/

Crispr Goes Global

http://vcresearch.berkeley.edu/news/profile/doudna_jennifer

UPDATED 3/5/2014

Double Nicking by RNA-Guided CRISPR Cas9 for Enhanced Genome Editing Specificity

http://www.cell.com/retrieve/pii/S0092867413010155

One-Step Generation of Mice Carrying Mutations in Multiple Genes by CRISPR/Cas-Mediated Genome Engineering

http://www.cell.com/retrieve/pii/S0092867413004674

RNA-Guided Human Genome Engineering via Cas9

http://www.sciencemag.org/content/suppl/2013/01/03/science.1232033.DC1

SOURCE

From: Expert CRISPR/Cas9 Publications <Expert_CRISPRCas9_Publications@mail.vresp.com>
Date: Tue, 04 Mar 2014 17:03:01 +0000
To: <avivalev-ari@alum.berkeley.edu>
Subject: CRISPR-mediated gene editing resources

 

UPDATED on 11/10/2013

Exclusive: ‘Jaw-dropping’ breakthrough hailed as landmark in fight against hereditary diseases as Crispr technique heralds genetic revolution

Development to revolutionise study and treatment of a range of diseases from cancer, incurable viruses such as HIV to inherited genetic disorders such as sickle-cell anaemia and Huntington’s disease

SCIENCE EDITOR

Thursday 07 November 2013

A breakthrough in genetics – described as “jaw-dropping” by one Nobel scientist – has created intense excitement among DNA experts around the world who believe the discovery will transform their ability to edit the genomes of all living organisms, including humans.

Click image above to enlarge graphic

The development has been hailed as a milestone in medical science because it promises to revolutionise the study and treatment of a range of diseases, from cancer and incurable viruses to inherited genetic disorders such as sickle-cell anaemia and Down syndrome.

For the first time, scientists are able to engineer any part of the human genome with extreme precision using a revolutionary new technique called Crispr, which has been likened to editing the individual letters on any chosen page of an encyclopedia without creating spelling mistakes. The landmark development means it is now possible to make the most accurate and detailed alterations to any specific position on the DNA of the 23 pairs of human chromosomes without introducing unintended mutations or flaws, scientists said.

The technique is so accurate that scientists believe it will soon be used in gene-therapy trials on humans to treat incurable viruses such as HIV or currently untreatable genetic disorders such as Huntington’s disease. It might also be used controversially to correct gene defects in human IVF embryos, scientists said.

Until now, gene therapy has had largely to rely on highly inaccurate methods of editing the genome, often involving modified viruses that insert DNA at random into the genome – considered too risky for many patients.

The new method, however, transforms genetic engineering because it is simple and easy to edit any desired part of the DNA molecule, right down to the individual chemical building-blocks or nucleotides that make up the genetic alphabet, researchers said.

“Crispr is absolutely huge. It’s incredibly powerful and it has many applications, from agriculture to potential gene therapy in humans,” said Craig Mello of the University of Massachusetts Medical School, who shared the 2006 Nobel Prize for medicine for a previous genetic discovery called RNA interference.

“This is really a triumph of basic science and in many ways it’s better than RNA interference. It’s a tremendous breakthrough with huge implications for molecular genetics. It’s a real game-changer,” Professor Mello told The Independent.

“It’s one of those things that you have to see to believe. I read the scientific papers like everyone else but when I saw it working in my own lab, my jaw dropped. A total novice in my lab got it to work,” Professor Mello said.

In addition to engineering the genes of plants and animals, which could accelerate the development of GM crops and livestock, the Crispr technique dramatically “lowers the threshold” for carrying out “germline” gene therapy on human IVF embryos, Professor Mello added.

The new method of gene therapy makes it simple and easy to edit any desired part of the DNA molecule (Getty Creative)

The new method of gene therapy makes it simple and easy to edit any desired part of the DNA molecule (Getty Creative) Germline gene therapy on sperm, eggs or embryos to eliminate inherited diseases alters the DNA of all subsequent generations, but fears over its safety, and the prospect of so-called “designer babies”, has led to it being made illegal in Britain and many other countries.

The new gene-editing technique could address many of the safety concerns because it is so accurate. Some scientists now believe it is only a matter of time before IVF doctors suggest that it could be used to eliminate genetic diseases from affected families by changing an embryo’s DNA before implanting it into the womb.

“If this new technique succeeds in allowing perfectly targeted correction of abnormal genes, eliminating safety concerns, then the exciting prospect is that treatments could be developed and applied to the germline, ridding families and all their descendants of devastating inherited disorders,” said Dagan Wells, an IVF scientist at Oxford University.

“It would be difficult to argue against using it if it can be shown to be as safe, reliable and effective as it appears to be. Who would condemn a child to terrible suffering and perhaps an early death when a therapy exists, capable of repairing the problem?” Dr Wells said.

The Crispr process was first identified as a natural immune defence used by bacteria against invading viruses. Last year, however, scientists led by Jennifer Doudna at the University of California, Berkeley, published a seminal study showing that Crispr can be used to target any region of a genome with extreme precision with the aid of a DNA-cutting enzyme called CAS9.

Since then, several teams of scientists showed that the Crispr-CAS9 system used by Professor Doudna could be adapted to work on a range of life forms, from plants and nematode worms to fruit flies and laboratory mice.

Earlier this year, several teams of scientists demonstrated that it can also be used accurately to engineer the DNA of mouse embryos and even human stem cells grown in culture. Geneticists were astounded by how easy, accurate and effective it is at altering the genetic code of any life form – and they immediately realised the therapeutic potential for medicine.

“The efficiency and ease of use is completely unprecedented. I’m jumping out of my skin with excitement,” said George Church, a geneticist at Harvard University who led one of the teams that used Crispr to edit the human genome for the first time.

“The new technology should permit alterations of serious genetic disorders. This could be done, in principle, at any stage of development from sperm and egg cells and IVF embryos up to the irreversible stages of the disease,” Professor Church said.

David Adams, a DNA scientist at the Wellcome Trust Sanger Institute in Cambridge, said that the technique has the potential to transform the way scientists are able to manipulate the genes of all living organisms, especially patients with inherited diseases, cancer or lifelong HIV infection.

“This is the first time we’ve been able to edit the genome efficiently and precisely and at a scale that means individual patient mutations can be corrected,” Dr Adams said.

“There have been other technologies for editing the genome but they all leave a ‘scar’ behind or foreign DNA in the genome. This leaves no scars behind and you can change the individual nucleotides of DNA – the ‘letters’ of the genetic textbook – without any other unwanted changes,” he said.

Timeline: Landmarks in DNA science

Restriction enzymes: allowed scientists to cut the DNA molecule at or near a recognised genetic sequence. The enzymes work well in microbes but are more difficult to target in the more complex genomes of plants and animals. Their discovery in the 1970s opened the way for the age of genetic engineering, from GM crops to GM animals, and led to the 1978 Nobel Prize for medicine.

Polymerase chain reaction (PCR): a technique developed in 1983 by Kary Mullis (below, credit: Getty) in California allowed scientists to amplify the smallest amounts of DNA – down to a single molecule – to virtually unlimited quantities. It quickly became a standard technique, especially in forensic science, where it is used routinely in analysing the smallest tissue samples left at crime scenes. Many historical crimes have since been solved with the help of the PCR test. Mullis won the Nobel Prize for chemistry in 1993.

RNA interference: scientists working on the changing colour of petunia plants first noticed this phenomenon, which was later shown to involve RNA, a molecular cousin to DNA. In 1998, Craig Mello and Andrew Fire in the US demonstrated the phenomenon on nematode worms, showing that small strands of RNA could be used to turn down the activity of genes, rather like a dimmer switch. They shared the 2006 Nobel Prize for physiology or medicine for the discovery.

Zinc fingers: complex proteins called zinc fingers, first used on mice in 1994, can cut DNA at selected sites in the genome, with the help of enzymes. Another DNA-cutting technique called Talens can do something similar. But both are cumbersome to use and difficult to operate in practice – unlike the Crispr technique.

VIEW VIDEO

http://www.independent.co.uk/news/science/indyplus-video-crispr-technique-8925604.html

a video of how the Crispr system derived from bacteria works on human cells to correct genetic defects

SOURCE

http://www.independent.co.uk/news/science/exclusive-jawdropping-breakthrough-hailed-as-landmark-in-fight-against-hereditary-diseases-as-crispr-technique-heralds-genetic-revolution-8925295.html?goback=%2Egde_2106240_member_5804987154979381248#%21

Jennifer A. Doudna

Professor of Chemistry
Professor of Biochemistry & Molecular Biology

email: doudna@berkeley.edu
office: 708A Stanley Hall
phone: 510-643-0225
fax: 510-643-0008

lab: 731 Stanley Hall
lab phone: 510-643-0113
lab fax: 510-643-0080

Research Group URL
Recent Publications

Research Interests

Chemical Biology

Ribozymes and RNA Machines: RNA forms a variety of complex globular structures, some of which function like enzymes or form functional complexes with proteins. There are three major areas of focus in the lab: catalytic RNA, the function of RNA in the signal recognition particle and the mechanism of RNA-mediated internal initiation of protein synthesis. We are interested in understanding and comparing catalytic strategies used by RNA to those of protein enzymes, focusing on self-splicing introns and the self-cleaving RNA from hepatitis delta virus (HDV), a human pathogen. We are also investigating RNA-mediated initiation of protein synthesis, focusing on the internal ribosome entry site (IRES) RNA from Hepatitis C virus. Cryo-EM, x-ray crystallography and biochemical experiments are focused on understanding the structure and mechanism of the IRES and its amazing ability to hijack the mammalian ribosome and associated translation factors. A third area of focus in the lab is the signal recognition particle, which contains a highly conserved RNA required for targeting proteins for export out of cells. Each of these projects seeks to understand the molecular basis for RNA function, using a combination of structural, biophysical and biochemical approaches.

Biography

Medical School, 1989-1991; Post-doctoral fellow, University of Colorado, 1991-1994; Assistant/Associate professor, (1994-1998), Professor, (1999-2001), Yale University. Professor of Biochemistry & Molecular Biology, UC Berkeley, (2002-). Howard Hughes Medical Investigator 1997 to present. Packard Foundation Fellow Award, 1996; NSF Alan T. Waterman Award, 2000. Member, National Academy of Sciences, 2002. Member, American Academy of Arts and Sciences, 2003; American Association for the Advancement of Science Fellow Award, 2008; Member, Institute of Medicine of the National Academies, 2010.

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Diagnosing Diseases & Gene Therapy: Precision Genome Editing and Cost-effective microRNA Profiling

https://pharmaceuticalintelligence.com/2013/03/28/diagnosing-diseases-gene-therapy-precision-genome-editing-and-cost-effective-microrna-profiling/

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Cell Transplantation in Brain Repair

Curator: Larry H Bernstein, MD, FCAP

Cell transplantation: relevance in understanding brain development and prospects in brain repair
M Jaber and A Gaillard
Experimental and Clinical Neurosciences Laboratory, INSERM, Poitiers, France
Front. Cell. Neurosci., 23 Nov 2012 |  http://dx. doi.org/10.3389/fncel.2012.00056
Neurodegenerative disorders such as Parkinson’s diseases (PD) and Huntington’s diseases (HD), neuronal injuries following trauma and neuronal cell death following strokes are major debilitating affections that are often accompanied by motor and cognitive dysfunctions with limited treatment options. Cell transplantation therapies have been considered for the last three decades as a serious avenue to explore with the ultimate aim to replace lost neurons with “new ones” initially originating from fetal neuroblasts and recently deriving from various sources of stem cells.
One of the many factors affecting the success of cell transplantation therapies is

  • host immune response to the graft.

This came as an evidence when attempts of cell therapy was undertaken with the use of human fetal neuroblasts or porcine fetal neuronal tissue for xenotransplantation in the human brain. Bonnamain et al. (2012) describe in this issue how this avenue led to disappointing results which damped this line of research. Pauly et al. (2012) focus on GABAergic striatal neurons with a detailed review on their development and clinical applications in HD. They report that in animal models of HD, the success of cellular transplantation with embryonic striatal transplants is influenced by many parameters. However, recent reports indicate that HD patients that underwent cell transplantation showed motor and cognitive improvements. Given that the use of fetal tissue as a cell source for neural transplantation is not without problems, a significant research activity has been oriented toward finding alternative sources of neural cells. Among these, pluripotent stem cells seem to be an obvious choice as these cells may differentiate into any cell type of any organ. As Benchoua and Onteniente (2012) put it in their review, pluripotent stem cells “hold the potential to revolutionize the field of neurodegenerative medicine by offering a robust and flexible source of allogenic or HLA compatible neuronal precursors.” In their review, the authors focus on

  •  regional and local patterning of these cells
  • to induce their differentiation into specific neural progenitors.

Then, they discuss safety issues regarding these cells,

  • factors that maintain their commitment after transplantation and
  • facilitate their integration within the host brain,
  • mostly in animal models of HD and PD.

The paper of Denham et al. (2012) reviews intra cerebral transplantation of neurons generated from

  •  human embryonic stem (hES) cells in
  • neonatal rats and focus on axonal growth in the host brain and
  • the corresponding electrophysiological properties.

They show that neurons generated from hES cells are capable of

  •  extensive growth within the host brain and
  • display properties consistent with functional integration
  • at the electrophysiological level.

these findings need to be replicated in the context of adult brain repair.

García-Parra et al. (2012) propose a study presenting a new polymeric support

  •  able to induce neuronal differentiation in both PC12 cell line and
  • adult primary skin-derived precursor cells in vitro.

They detail the use of a combined photolithographic technique

  •  to create a topography of micropatterned substrates composed of
  • extracellular matrix providing the cells with
  • appropriate cues for their differentiation.

Such models can set the basis for new avenues to explore the differentiation of stem cells

  •  in vitro after adjustment of the proper microenvironment
  • in order to obtain the requested specific neuronal subtype.

In the in vivo area, de Chevigny et al. (2012) present a very elegant study aimed at

  • characterizing the spatial and temporal expression of two major transcription factors,
  • Pax6 and DIx2 that are implicated in the generation of olfactory bulb (OB) neurons.

OB neurogenesis attracts attention as their

  •  dopamine neurons, or their precursors,
  • are presented as of potential interest in cell replacement or recruitment therapies in PD.

The dynamic expression data presented for these two transcription factors indicate that

  •  while Pax6 is implicated in OB dopaminergic cell fate in a specific and permanent manner,
  • DIx2 expression is more generalized and transient.

This method offers a better explanation of factors involved in the cell lineage of dopamine neurons, but more importantly, is helpful in identifying

  •  molecular mechanisms involved in neuronal subtype specification in the postnatal brain.

Following transplantation, axons derived from transplanted neurons

  •  need to find their way and innervate target areas.

Our own findings showed that embryonic mesencephalic dopamine neurons transplanted in the substantia nigra in an animal model of PD

  •  are able to extend axons toward the striatum (Gaillard et al., 2009; Gaillard and Jaber, 2011).

These results suggest that specific guidance cues exist in the adult brain and that

  •  axons from transplanted embryonic cells

are able to respond to theses cues, guiding them to their final targets.

The review by Prestoz et al. (2012) summarizes the current knowledge on

  •  the identity of cellular and molecular signals thought to be involved in development of the dopamine pathway during embryogenesis in the rodent central nervous system.

The paper also describes the modulation of these factors following lesion and transplantation and their potential implication in restoring damaged pathways.

The review by Saha et al. (2012) is focused on

  •  stimulation,
  • migration of the pools of neural stem or precursor cells,
  • particularly in the subventricular zone following cortical injuries, and
  • details the cellular and molecular mechanisms involved in these processes.

These range from

  •  molecular factors,
  • glial reaction,
  • vasculature
  • physical exercise.

The description is extended to future avenues that

  •  need to be explored in order to better induce these reactions, as
  • their efficiency in brain repair is very limited.

Although cell transplantation in the damaged brain is not likely to be routinely performed in the near future,

  •  the different paths that are evoked in this series of reviews should yield safer, more effective and physiologically relevant transplantation procedures.

References
Benchoua, A., and Onteniente, B. (2012). Intracerebral transplantation for neurological disorders. Lessons from developmental, experimental, and clinical studies.
Front. Cell. Neurosci. 6:2.            http://dx.doi.org/10.3389/fncel.2012.00002
Bonnamain, V., Neveu, I., and Naveilhan, P. (2012). Neural stem/progenitor cells as a promising candidate for regenerative therapy of the central nervous system.
Front. Cell. Neurosci. 6:17.     http://dx.doi.org/10.3389/fncel.2012.00017
de Chevigny, A., Core, N., Follert, P., Wild, S., Bosio, A., Yoshikawa, K., et al. (2012). Dynamic expression of the pro-dopaminergic transcription factors Pax6 and Dlx2 during postnatal olfactory bulb neurogenesis.
Front. Cell. Neurosci. 6:6.       http://dx.doi.org/10.3389/fncel.2012.00006
Denham, M., Parish, C. L., Leaw, B., Wright, J., Reid, C. A., Petrou, S., et al. (2012). Neurons derived from human embryonic stem cells extend long-distance axonal projections through growth along host white matter tracts after intra-cerebral transplantation.
Front. Cell. Neurosci. 6:11.       http://dx.doi.org/10.3389/fncel.2012.00011
Gaillard, A., Decressac, M., Frappé, I., Fernagut, P. O., Prestoz, L., Besnard, S., et al. (2009). Anatomical and functional reconstruction of the nigrostriatal pathway by intranigral transplants. Neurobiol. Dis. 35, 477–488.
Gaillard, A., and Jaber, M. (2011). Rewiring the brain with cell transplantation in Parkinson’s disease. Trends Neurosci. 34, 124–133.
García-Parra, P., Cavaliere, F., Maroto, M., Bilbao, L., Obieta, I., López de Munain, A., et al. (2012). Modeling neural differentiation on micropatterned substrates coated with neural matrix components.
Front. Cell. Neurosci. 6:10.       http://dx.do.org/10.3389/fncel.2012.00010
Pauly, M. C., Piroth, T., Döbrössy, M., and Nikkhah, G. (2012). Restoration of the GABAergic striatal circuitry: from developmental aspects towards clinical applications.
Front. Cell. Neurosci. 6:16.        http://dx.doi.org/10.3389/fncel.2012.00016
Prestoz, L., Jaber, M., and Gaillard, A. (2012). Dopaminergic axon guidance: which makes what? Front. Cell. Neurosci. 6:32.               http://dx.doi.org/10.3389/fncel.2012.00032. 

Saha, B., Jaber, M., and Gaillard, A. (2012). Potentials of endogenous neural stem cells in brain repair. Front. Cell. Neurosci. 6:14.   http://dx.doi.org/10.3389/fncel.2012.00014

Citation: Jaber M and Gaillard A (2012) Cell transplantation: relevance in understanding brain development and prospects in brain repair. Front. Cell. Neurosci. 6:56. http://dx.doi.org/10.3389/fncel.2012.00056

Stem cell diagram illustrates a human fetus st...

Stem cell diagram illustrates a human fetus stem cell and possible uses on the circulatory, nervous, and immune systems. (Photo credit: Wikipedia)

English: Complete neuron cell diagram. Neurons...

English: Complete neuron cell diagram. Neurons (also known as neurones and nerve cells) are electrically excitable cells in the nervous system that process and transmit information. In vertebrate animals, neurons are the core components of the brain, spinal cord and peripheral nerves. (Photo credit: Wikipedia)

B0003894 NMDA receptors in the brain

B0003894 NMDA receptors in the brain (Photo credit: wellcome images)

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