New Investigator of the Month

Who are the faces of ASGCT?

ASGCT's New Investigator of the Month profiles an ASGCT member who is new to the field or just beginning an independent position. To be considered for a future New Investigator of the Month, applicants must be an Active or Associate Member of the Society. Active Members must be 10 or fewer years out from their first active, independent position.

Please click here to apply or nominate a colleague. New Investigators of the Month are selected by the ASGCT New Investigator Committee.

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Questionnaire

Briefly describe your current research interests.

My current research interests involve screening of DNA shuffled AAV libraries to screen for novel vectors that are capable of transducing specific cell populations of the central nervous system.

When and why did you first develop an interest in gene and cell therapies?

 In 2009, I joined the lab of Miguel Sena-Esteves at the University of Massachusetts Medical School as a doctoral candidate, where I am currently. Our lab focuses on gene therapy of central nervous system disorders, particularly using AAV vectors, and this is where I picked up my interest in development of better AAV vectors for gene therapy.

What, in your opinion, marks the greatest advance to date in the field of gene and cell therapy and why?

In terms of total impact on the field, Paul Berg's attempts to transfer lambda bacteriophage DNA to monkey kidney cells using SV40 virus was perhaps the most important as it was one of the first attempts of using viral vectors for gene therapy. It also led to the development of the 'cut-and-splice' method of cloning recombinant DNA used ubiquitously to this day and in addition led to a public debate on science policy and regulation of biotechnology research, culminating in the guidelines developed during the Asilomar Conference. More recently, the development of AAV vectors for gene transfer was very important. These are replication-defective, do not integrate into the host genome and have a low immunogenic profile. These are almost every characteristic of the ideal viral vector.

In your opinion, what are the greatest areas of need which must be addressed to ensure continued progress in this field?

Understanding vector transduction of cells at a molecular level (such as identification of novel receptors/co-receptors on cell surface for vector binding and endocytosis) to develop vectors targeted to a more specific cell population is one such field. Rational cell type-specific promoter/enhancer element design for transgenes is another. Modulating host responses to vector, such as reducing (or enhancing, as the case may be) the immumogenicity of vector or transgene is a third area.

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Questionnaire

Briefly describe your current research interests.

My current research interests are in the area of retroviral/lentiviral vector integration studies in gene therapy clinical trials. In particular, my research projects are based on the exploitation of gene therapy patients’ “integrome” as a unique barcode-based model to study hematopoietic system biology in vivo at single clone level in humans.

When and why did you first develop an interest in gene and cell therapies?

I graduated in Biotechnology at Alma Mater Studiorum University of Bologna in 2003 and worked for 2 years as fellow on pediatric leukemias. During this period I spent 2 months at the National Institutes of Health (NIH) in Bethesda studying the impact of decitabine and valproic acid on acute myeloid leukemia cells transcriptome by custom microarrays.

My first contact with gene therapy (GT) was in 2005 when I moved from Bologna to Milan to start a PhD in the group leaded by Prof. Alessandro Aiuti at HSR-TIGET. By that time gene therapy field was in jeopardy due to the reports of the first cases of leukemias originated from insertional mutagenesis in GT clinical trials for severe combined immunodeficiencies (SCID). During my first years at TIGET I was able to assess the safety of retroviral gene therapy for ADA-SCID by retrieving integration sites and studying their distribution in vivo in treated patients. I also shed light on vector-host interactions uncovering a target-cell dependent IS distribution of retroviral vectors and the genetic and epigenetic factors influencing the cell-specific genomic localization of proviral insertions.

What, in your opinion, marks the greatest advance to date in the field of gene and cell therapy and why?

One of the major advances in gene therapy field achieved in the past 5 years is represented by the design and the successful clinical exploitation of a new generation of retrovirus-based vectors that combine strong transduction efficiency with a finely regulated transgene expression and a safer insertional profile, able to overcome the limitation of the first vector platforms.
  Question 6 txt: One of my favorite quote says: ” Big data is like teenage sex: everyone talks about it, nobody really knows how to do it, everyone thinks everyone else is doing it, so everyone claims they are doing it”

The next years will see an increasing impact of deep sequencing for the screening of novel gene-transfer technologies and the follow-up of gene therapy clinical trials. There will thus be an increasing demand for a proper integration of bioinformatics and biology with the development of specific in silico platforms for data manipulation and analysis. However, gene therapist should at the same time become educated to preserve their hypothesis-driven approach to biological questions in order to avoid the risk of “datafication” and correlation/causation distortions inherent to the potential overflow of data from deep sequencing technologies.

In light of your accomplishments, what advice would you offer to your ASGCT colleagues with respect to research and/or career development?

Commitment and endurance are always the key words. However, I also believe that research is still about having fun and enjoying the discovery process. Whatever is your career plan I suggest you to always keep alive the young spirit of wondering and speculating that makes this job unique.

How do you like to pass the time outside of work?

During my free time I love doing sports on a daily basis like biking and running, weekly like soccer and seasonally like snowboarding and surfing. I also love music and I own an acoustic and an electric guitar that I enjoying playing whenever I can.

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Questionnaire

Briefly describe your current research interests.

My principal research interests are in the areas of pancreatic physiology, differentiation and pancreatic cancer and that the transcription factor PDX-1 plays a key role in determining cell lineages in the pancreas also plays a pro-oncogenic role in the development of pancreatic cancer.

Briefly describe how you reached your current posiiton (educational background)

 I am a gastrointestinal surgeon-scientist who trained at SUNY Brooklyn Health and Science Center, Brooklyn, during which time I did a three year research fellowship in pancreas physiology. As an assistant professor, I became a member of the CURE: DDRC from 1989 to 1995 to study somatostatin receptors and then was recruited in 1995 to Baylor College of Medicine in Houston, Texas as George Jordan Professor and Chief of General Surgery. In 1999, Brunicardi became DeBakey/Bard Professor and Chairman of the Michael E. DeBakey Department of Surgery at Baylor and held that leadership position for 12 years. In 2011, Dr. Brunicardi rejoined the UCLA faculty as Moss Foundation Chair in Gastrointestinal and Personalized surgery, Professor and Chief of the Santa Monica-UCLA General Surgery Group and a Vice Chair of the Department of Surgery for Surgical Services at Santa Monica-UCLA Medical Center. At the same time, Dr. Brunicardi also rejoined the CURE: DDRC where his laboratory is located.

When and why did you first develop an interest in gene and cell therapies?

My lab had cloned mouse somatostatin receptor subtype and developed an SSTR5-/- mouse model. We were using the rat insulin promoter for the development of the mice, therefore began using RIP to engineer insulinoma and pancreas cancer cells. We determined that PDX1 was the major factor activating RIP and began studying PDX1 in pancreas cancer.

What do you view as your greatest scientific achievement to date?

The finding that PDX1 is an oncogenic transcription factor and a therapeutic target for pancreatic cancer using PDX1 RNAi therapy.

What, in your opinion, marks the greatest advance to date in the field of gene and cell therapy and why?

There are so many, however the use of nanotechnology to deliver genes and RNAi is so important because it permits multiple intravenous applications of gene therapy and RNAi therapy.  Therefore, this therapy can now have practical applications to human disease.

In your opinion, what are the greatest areas of need which must be addressed to ensure continued progress in this field?

How to improve gene transfection efficiency using nanotechnology is the greatest area of need.

7) In what ways do you feel the ASGCT has played a role in your scientific and career development?

I am delighted to be a part of the ASGCT and find that the collaboration with ASGCT members will help bring PDX1 RNAi therapy to phase 1 clinical trials.

In light of your accomplishments, what advice would you offer to your ASGCT colleagues with respect to research and/or career development?

The two keys are vision and persistence over a very long period of time. Dr. Walsh taught me that if drawing a model of your research vision is of enormous help in defining the vision.

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Questionnaire

Briefly describe your current research interests.

From a gene therapy standpoint, my lab is focused on developing RNAi-based treatments for dominantly inherited neuromuscular disorders.  We are also pursuing basic mechanistic studies related to two such disorders:  Facioscapulohumeral Muscular Dystrophy (FSHD) and Limb-Girdle Muscular Dystrophy Type 1A (LGMD1A).

Briefly describe how you reached your current posiiton (educational background)

I am a veteran of the U.S. Naval Reserve.  I used my GI Bill funds to support a B.S. in Biology from Saginaw Valley State University, which I earned in 1996.  During my undergraduate years, I also worked in a polymer chemistry lab at the Dow Chemical Company in Midland, Michigan.  I was then admitted to the Cell and Molecular Biology Graduate Program at the University of Michigan and joined Dr. Jeffrey Chamberlain's lab in 1997, where I worked on developing the first generation of micro-dystrophins for treatment of Duchenne Muscular Dystrophy.  During my 4th year of graduate school, Dr. Chamberlain moved his lab to the University of Washington, and I relocated with him to Seattle in December of 2000.  I defended my PhD back in Ann Arbor in April of 2002 and then joined Dr. Beverly Davidson's lab at the University of Iowa as a post-doc in May of that year.  With Dr. Davidson and my colleagues in the Davidson lab, I worked to develop the first generation of RNAi-based gene therapy vectors to treat Huntington's disease.  In July 2007, I began my first faculty position with a joint appointment as an Assistant Professor of Pediatrics at the Ohio State University and Principal Investigator in the Center for Gene Therapy at The Research Institute at Nationwide Children's Hospital.

When and why did you first develop an interest in gene and cell therapies?

 I was inspired to pursue work in the gene therapy field almost immediately after beginning my lab rotation with Dr. Chamberlain in early 1997.  Jeff was a huge influence.  He was doing "translational research" before the term existed by studying basic aspects of dystrophin biology and applying that knowledge to develop rational and targeted therapies for DMD.  I consider him to be one of the great pioneers of the muscle gene therapy field.

In your opinion, what are the greatest areas of need which must be addressed to ensure continued progress in this field?

Certainly, there are several areas of need.  One comes to mind first because of two interactions I've had in recent months with representatives of some private companies who were interested in the goals of our work but not the fact that we were using gene therapy approaches to accomplish them.  Now perhaps these were minority opinions, but I suspect that the negative perception of gene therapy is pervasive.  So, from my perspective, I think we need to continue working to change the unwarranted negative perceptions that exist about our field.  

Let's face it, gene therapy has been a victim of unrealistic expectations since the field began.  I was struck by an old and prescient commentary I recently read called "Molecular biology, nucleic acids, and the future of medicine", which was authored Nobel Prize winner E.L. Tatum in 1966.  Tatum predicted the emergence of genetic screening, cloning of disease genes, and the use of viral vectors for gene delivery.  Interestingly, related to my own interests with RNAi therapy, he also predicted that "harmful dominant genes could be repressed as desired" using a "yet to be discovered" compound.  What is even more remarkable about Tatum's commentary was that it was published 6 years before the tools to clone DNA were even available.  Despite being spot on with these prognostications, he was wrong about the timeline:  he suggested all this would be achieved within 20 years of his writing, which would have been around the time that the first gene was positionally cloned.  So there was early hype for gene therapy even before the field existed.

Then once "recombinant DNA" became possible, the spotlight on gene therapy became brighter fast.  The concept seemed straightforward enough that expectations were raised (in some scientists and non-scientists alike) for rapid cures.  So once again, at the very outset, there were unrealistic expectations about what would and could be achieved immediately.  When gene therapy cures didn't arrive right away, and some bumps in the road were encountered (which should have been anticipated for any nascent field), I think it's fair to say gene therapy was the recipient of mostly unwarranted negative perceptions.  Today, we're now seeing new commentaries heralding the comeback of gene therapy.  Although I understand and agree with those positive sentiments, I would argue our field never needed a comeback.  Instead, I'd say the field has been mostly on a steady incline for more than 20 years and we are now entering an exciting era where things are starting to come together.  I think now is the time to legitimately hype our field, and I am doing it every chance I get.

How do you pass the time outside of work?

I am married and have three kids, ages 15, 12, and 8.  Outside of work, my wife and I spend a lot of time shuttling kids to piano lessons, or to lacrosse, ice hockey, and volleyball practices and tournaments.  This schedule doesn't allow time for much else.

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Questionnaire

Briefly describe your current research interests.

The field of gene therapy is at a decisive point in time. The increased understanding of the complex biology of gene transfer together with the improved vector technologies have made it that the first genuine successes in the clinic are being observed. The question now remains whether applications of gene therapy are going to be restricted to few niche indications or whether it can become a true therapeutic platform. My laboratory tries to identify, study and then hopefully develop technologies to overcome hurdles for gene therapy to widen its reach. For example, our research on AAV  tries to study the packaging limitation of AAV in the hope to increase AAV's genetic cargo capacity. Another example is our interest to develop a gene therapy for retinal blindness independent of the disease etiology or genetic insult by using optogenetics.

Briefly describe how you reached your current posiiton (educational background)

I am a biological engineer in cellular and genetic biotechnology from the Katholieke Universiteit Leuven in Belgium. In the final year I was selected to do my thesis research in the Rega laboratory for virology and immunology, where I worked on small molecule inhibition of Tat and Rev of HIV-1. This is where I became fascinated with virology, and especially HIV. I then came to University of Pennsylvania in Philadelphia, PA where I worked in the laboratory of Dr. Carl June, MD on Chimeric Antigen Receptor strategies as well as lentiviral vector development.  For my PhD in Molecular Medicine, I trained in the laboratory of Dr. James M. Wilson at Penn where I worked on the discovery and biology of novel AAV serotypes. I stayed on in Dr. Wilson's lab for several more years working on AAV immunology, vector development and translation, with a focus on retinal gene transfer. Finally, I worked closely with Dr. Jean Bennett at Penn for many years on AAV gene transfer to the retina and novel translational approaches for blindness gene therapy.

What, in your opinion, marks the greatest advance to date in the field of gene and cell therapy and why?

Without a doubt, the creation of replication-defective viruses for gene transfer.

In your opinion, what are the greatest areas of need which must be addresed to ensure continued progress in the field?

There is a critical need to think of all aspects of gene therapy in the marketplace. For gene therapy to succeed, it ultimately needs to be adopted by the pharmaceutical industry. For industry to invest in this technology, economical and regulatory questions need to be addressed and probably new frameworks need to be developed. How do we price a gene therapy drug? How do we reimburse orphan disease drugs, especially when more enter the market? How do we incentivize the development of single dose drugs over regimen pharmaceuticals?
 

How do you pass the time outside of work?

I have two young daughters whom I love to spend time with.

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