Posts Tagged ‘Duchenne muscular dystrophy’

Real Time Coverage @BIOConvention #BIO2019: Genome Editing and Regulatory Harmonization: Progress and Challenges

Reporter: Stephen J Williams, PhD @StephenJWillia2


Genome editing offers the potential of new and effective treatments for genetic diseases. As companies work to develop these treatments, regulators are focused on ensuring that any such products meet applicable safety and efficacy requirements. This panel will discuss how European Union and United States regulators are approaching therapeutic use of genome editing, issues in harmonization between these two – and other – jurisdictions, challenges faced by industry as regulatory positions evolve, and steps that organizations and companies can take to facilitate approval and continued efforts at harmonization.


CBER:  because of the nature of these gene therapies, which are mainly orphan, there is expedited review.  Since they started this division in 2015, they have received over 1500 applications.

Spark: Most of the issues were issues with the primary disease not the gene therapy so they had to make new endpoint tests so had talks with FDA before they entered phase III.   There has been great collaboration with FDA,  now they partnered with Novartis to get approval outside US.  You should be willing to partner with EU pharmas to expedite the regulatory process outside US.  In China the process is new and Brazil is behind on their gene therapy guidance.  However there is the new issue of repeat testing of your manufacturing process, as manufacturing of gene therapies had been small scale before. However he notes that problems with expedited review is tough because you don’t have alot of time to get data together.  They were lucky that they had already done a randomized trial.

Sidley Austin:  EU regulatory you make application with advance therapy you don’t have a national option, the regulation body assesses a committee to see if has applicability. Then it goes to a safety committee.  EU has been quicker to approve these advance therapies. Twenty five percent of their applications are gene therapies.  Companies having issues with manufacturing.  There can be issues when the final application is formalized after discussions as problems may arise between discussions, preliminary applications, and final applications.

Sarepta: They have a robust gene therapy program.  Their lead is a therapy for DMD (Duchenne’s Muscular Dystrophy) where affected males die by 25. Japan and EU have different regulatory applications and although they are similar and data can be transferred there is more paperwork required by EU.  The US uses an IND for application. Global feedback is very challenging, they have had multiple meetings around the world and takes a long time preparing a briefing package….. putting a strain on the small biotechs.  No company wants to be either just EU centric or US centric they just want to get out to market as fast as possible.


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4:00PM 11/12/2014 – 10th Annual Personalized Medicine Conference at the Harvard Medical School, Boston

REAL TIME Coverage of this Conference by Dr. Aviva Lev-Ari, PhD, RN – Director and Founder of LEADERS in PHARMACEUTICAL BUSINESS INTELLIGENCE, Boston

4:00 p.m. Panel Discussion Novel Approaches to Personalized Medicine

Novel Approaches to Personalized Medicine

Genetic and genomic knowledge is helping the development of new drugs, therapies and prognostic tests. As a result, there are new approaches, new partnerships and new business models that are emerging. In some cases, diseases that were considered incurable not too long ago are now being tackled with highly targeted therapies. In other cases the uncertainties associated with assessing potential aggressiveness of disease are being eliminated. This panel will provide examples of new business paradigms that are emerging from the application of personalized medicine.

Novel Approaches to Personalized Medicine


Meghan FitzGerald, Ph.D. @cardinalhealth
President, Cardinal Health Specialty Solutions

Chief Genome Officer – next steps in companies, Genomics Index will replace the Biotech Index

Most Interesting person in Genomics: Marc Levin,


2. Chris Garabedian @Sarepta
President and CEO, Sarepta

  • Applications of genomics to Infectious diseases, therapeutics – design of drugs, Duchenne Muscular Dystrophy (DMD)
  • technology safe working, one drug very effective, 60 alternative drugs, not enough patients to power clinical trials


4. Shawn Marcell
President & CEO, Metamark Genetics

  • Prostatic Cancer – Use of genomics tools to diagnose and treat Prostate cancer
  • US market is the best for Genomics innovations because venture capital Market is mature, FDA is negotiable, CMP well established
  • Business model: platform, good test big market, commercialize, clinical data — PM has a different Business model: Delivery of Test results need to be different
  • IPO 2016


1. Scott Schell, M.D., Ph.D. – surgical oncology @KEWGroup
President and CEO, KEW Group

  • Large scale platform, strategic partnerships with Oncology Practices,
  • Immuno oncologists, repository of data
  • 80% of cancers are treated in the community 20% at Academic centers. Integration of knowledge, patients wish to stay in the community
  • phase I approval at record high levels

3. Gabriel Bien-Willner, M.D., Ph.D. @MolecularHealth
Medical Director, MolecularHealth, Inc.

  • Diagnostics Tools in Analytics. Clinicians do not have the training in Genomics – position firm to create Lab reports and consulting MDs using Analytics for Clinicians



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Reporter: Aviva Lev-Ari, PhD, RN


Nature Genetics (2013) doi:10.1038/ng.2705

Independent specialization of the human and mouse X chromosomes for the male germ line

  1. Whitehead Institute, Cambridge, Massachusetts, USA.

    • Jacob L Mueller,
    • Helen Skaletsky,
    • Laura G Brown,
    • Sara Zaghlul &
    • David C Page
  2. Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Helen Skaletsky,
    • Laura G Brown &
    • David C Page
  3. The Genome Institute, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Susan Rock,
    • Tina Graves,
    • Wesley C Warren &
    • Richard K Wilson
  4. The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Katherine Auger
  5. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • David C Page


J.L.M., H.S., W.C.W., R.K.W. and D.C.P. planned the project. J.L.M. and L.G.B. performed BAC mapping. J.L.M. performed RNA deep sequencing. T.G., S.R., K.A. and S.Z. were responsible for finished BAC sequencing. J.L.M. and H.S. performed sequence analyses. J.L.M. and D.C.P. wrote the manuscript.

Competing financial interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to:

Nature Genetics (2013) doi:10.1038/ng.2705


 11 February 2013 Accepted

20 June 2013 Published online

21 July 2013

We compared the human and mouse X chromosomes to systematically test Ohno’s law, which states that the gene content of X chromosomes is conserved across placental mammals1. First, we improved the accuracy of the human X-chromosome reference sequence through single-haplotype sequencing of ampliconic regions. The new sequence closed gaps in the reference sequence, corrected previously misassembled regions and identified new palindromic amplicons. Our subsequent analysis led us to conclude that the evolution of human and mouse X chromosomes was bimodal. In accord with Ohno’s law, 94–95% of X-linked single-copy genes are shared by humans and mice; most are expressed in both sexes. Notably, most X-ampliconic genes are exceptions to Ohno’s law: only 31% of human and 22% of mouse X-ampliconic genes had orthologs in the other species. X-ampliconic genes are expressed predominantly in testicular germ cells, and many were independently acquired since divergence from the common ancestor of humans and mice, specializing portions of their X chromosomes for sperm production.

Refined X Chromosome Assembly Hints at Possible Role in Sperm Production

July 22, 2013

NEW YORK (GenomeWeb News) – A US and UK team that delved into previously untapped stretches of sequence on the mammalian X chromosome has uncovered clues that sequences on the female sex chromosome may play a previously unappreciated role in sperm production.

The work, published online yesterday in Nature Genetics, also indicated such portions of the X chromosome may be prone to genetic changes that are more rapid than those described over other, better-characterized X chromosome sequences.

“We view this as the double life of the X chromosome,” senior author David Page, director of the Whitehead Institute, said in a statement.

“[T]he story of the X has been the story of X-linked recessive diseases, such as color blindness, hemophilia, and Duchenne’s muscular dystrophy,” he said. “But there’s another side to the X, a side that is rapidly evolving and seems to be attuned to the reproductive needs of males.”

As part of a mouse and human X chromosome comparison intended to assess the sex chromosome’s similarities across placental mammals, Page and his colleagues used a technique called single-haplotype iterative mapping and sequencing, or SHIMS, to scrutinize human X chromosome sequence and structure in more detail than was available previously.

With the refined human X chromosome assembly and existing mouse data, the team did see cross-mammal conservation for many X-linked genes, particularly those present in single copies. But that was not the case for a few hundred species-specific genes, many of which fell in segmentally duplicated, or “ampliconic,” parts of the X chromosome. Moreover, those genes were prone to expression by germ cells in male testes tissue, pointing to a potential role in sperm production-related processes.

“X-ampliconic genes are expressed predominantly in testicular germ cells,” the study authors noted, “and many were independently acquired since divergence from the common ancestor of humans and mice, specializing portions of their X chromosomes for sperm production.”

The work was part of a larger effort to look at a theory known as Ohno’s law, which predicts extensive X-linked gene similarities from one placental mammal to the next, Page and company turned to the same SHIMS method they used to get a more comprehensive view of the Y chromosome for previous studies.

Using that sequencing method, the group resequenced portions of the human X chromosome, originally assembled from a mishmash of sequence from the 16 or more individuals whose DNA was used to sequence the human X chromosome reference.

Their goal: to track down sections of segmental duplication, called ampliconic regions, that may have been missed or assembled incorrectly in the mosaic human X chromosome sequence.

“Ampliconic regions assembled from multiple haplotypes may have expansions, contractions, or inversions that do not accurately reflect the structure of any extant haplotype,” the study’s authors explained.

“To thoroughly test Ohno’s law,” they wrote, “we constructed a more accurate assembly of the human X chromosome’s ampliconic regions to compare the gene contents of the human and mouse X chromosomes.”

The team focused their attention on 29 predicted ampliconic regions of the human X chromosome, using SHIMS to generate millions of bases of non-overlapping X chromosome sequence.

With that sequence in hand, they went on to refine the human X chromosome assembly before comparing it with the reference sequence for the mouse X chromosome, which already represented just one mouse haplotype.

The analysis indicated that 144 of the genes on the human X chromosome don’t have orthologs in mice, while 197 X-linked mouse genes lack human orthologs.

A minority of those species-specific genes arose as the result of gene duplication or gene loss events since the human and mouse lineages split from one around 80 million years ago, researchers determined. But most appear to have resulted from retrotransposition or transposition events involving sequences from autosomal chromosomes.

And when the team used RNA sequencing and existing gene expression data to look at which mouse and human tissues flip on particular genes, it found that many of the species-specific genes on the X chromosome showed preferential expression in testicular cells known for their role in sperm production.

Based on such findings, the study’s authors concluded that “the gene repertoires of the human and mouse X chromosomes are products of two complementary evolutionary processes: conservation of single-copy genes that serve in functions shared by the sexes and ongoing gene acquisition, usually involving the formation of amplicons, which leads to the differentiation and specialization of X chromosomes for functions in male gametogenesis.”

The group plans to incorporate results of its SHIMS-based assembly into the X chromosome portion of the human reference genome.

“This is a collection of genes that has largely eluded medical geneticists,” the study’s first author Jacob Mueller, a post-doctoral researcher in Page’s Whitehead lab, said in a statement. “Now that we’re confident of the assembly and gene content of these highly repetitive regions on the X chromosome, we can start to dissect their biological significance.”

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