The Vector

Volume 7, Issue 6: July 2018

Editorial Team

Phillip Doerfler, PhD - Editor, The Vector
Melvin Rincon, MD, PhD - Associate Editor, The Vector
Edith Pfister, PhD - Junior Editor, The Vector

Inside This Issue

President's Message
Breaking Through
Society News
Public Policy
Industry News

Editor's Message

Scientist and physician George Stamatoyannopoulos, who conceptualized and helped create the American Society of Gene & Cell Therapy in 1996, died June 16, 2018. To those who knew Dr. Stamatoyannopoulos, he was a friend, mentor, leader, and brilliant scientist.

He was born in Athens on March 11, 1934. Despite many difficulties in his childhood caused by regional turmoil and the separation of his family, he completed a classical education by studying science at night. He completed medical school in Athens, graduating top of his class. He then acquired an MA in Clinical Therapeutics from the same school and the National Research Foundation, and received a doctorate from the Medical School, in 1960.

ASGCT was established in 1996 by Dr. Stamatoyannopoulos, professor of medicine at the University of Washington's School of Medicine, and a group of the country's leading researchers in gene therapy. Dr. Stamatoyannopoulos felt there was a need for a professional society specifically devoted to gene therapy. We have his foresight to thank for the ever-growing field gene and cell therapy has become. Dr. Stamatoyannopoulos became ASGCT’s first president, holding that term until 1998. In 1999, the Society honored him by creating an annual lecture in his name. He was instrumental in founding ASGCT as well as helping the society and the field through more difficult years. Dr. Stamatoyannopoulos made lasting contributions in both research and in the creation of a Society, with nearly 3,000 members, which continues to connect individuals involved in gene and cell therapy research.

In 2017, Dr. Stamatoyannopoulos was awarded the Sonia Skarlatos, PhD, Public Service Award. His research work spans a variety of areas of human genetics and genetic hematology, including population genetics, impact of genetic counseling, the structure and function of hemoglobinopathies, the genetics of thalassemia syndromes, and the analysis of the molecular and cellular control of globin gene switching. He served on more than a dozen editorial boards while authoring more than 420 scientific papers and 14 books. In the last 20 years, his research focused on the development of gene therapy for hemoglobinopathies and other disorders that can be cured by gene transfer into stem cells. His interest in population genetics included the genetics of the Bronze Age population of the Minoans and the Mycenaean’s and the genetics of the populations of Greece and the Balkan Peninsula. I only met Dr. Stamatoyannopoulos a few times, but it was clear he was the consummate scholar and strong supporter of scientific discovery at every level, encouraging and excited at every new discovery whether that be a graduate student’s first poster or a keynote presentation. His passing will leave an empty space in the world, not soon to be filled.

Dr. Stamatoyannopoulos will be missed by his friends and colleagues.


Phil Doerfler, PhD

Breaking Through

AAV5-miHTT gene therapy demonstrates broad distribution and strong human mutant huntingtin lowering in a Huntington disease minipig model

Evers, Melvin M. et al.
Molecular Therapy, Published Online: June 25, 2018

Summary by: Melvin M. Evers1
Department of Research & Development, uniQure biopharma B.V., Amsterdam, the Netherlands, Email:

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the first exon of the huntingtin (HTT) gene. The CAG expansion in the HTT gene results in a prolonged polyglutamine repeat in the huntingtin protein that acquires toxic properties, affecting numerous cellular processes 1. Neurodegeneration starts in the forebrain and specifically affects the striatal complex; the caudate nucleus and putamen, thereby disrupting cortico-striatal pathways. Disruption of these cortico-striatal pathways in HD leads to impairment of cognition, motor function and behavior 1.

Since the culprit of the disease is the expanded polyglutamine-containing huntingtin protein, strategies to lower the mutant huntingtin protein can potentially modify the progression of the disease. Preclinical studies in HD rodent models have demonstrated that lowering mutant huntingtin protein reduces downstream deleterious effects 2,3. Most approaches of huntingtin-lowering aim to decrease translation of huntingtin exploiting the endogenous RNA interference (RNAi) mechanism by using synthetic small interfering RNA (siRNA), short hairpin RNA (shRNA), and microRNA (miRNA), or by using modified single-stranded antisense oligonucleotides 2,3. Our group has previously demonstrated sustained suppression of huntingtin in HD rodents using a miRNA expressed from a one-time delivery of an adeno-associated virus serotype 5 (AAV5) gene therapy approach 4,5.

Translating preclinical studies in HD animal models to the clinic involves assessing the therapeutic window by evaluating distribution, efficacy, and tolerability. Although in many cases proof-of-concept in HD rodent models has been shown, thus far none of the proposed disease-modifying treatments could be translated fully to the clinic 2. One of the challenges of rodents as a model of neurodegenerative diseases is their relatively small brain, making successful translation to the HD patient difficult. This is particularly relevant for gene therapy approaches, where the achieved distribution upon local injection in the parenchyma is likely dependent on brain size and structure. To overcome this issue, a great effort has been put in the establishment of larger animal models of HD, such as sheep, monkey and minipig models 6.

In the current study, we aimed to demonstrate the translation of huntingtin-lowering gene therapy approach to a large animal brain, the transgenic HD (tgHD) minipig. In addition to porcine huntingtin, the tgHD minipig model ubiquitously expresses an N-terminal human huntingtin fragment containing 124 glutamines 7. Pigs have a brain structure and blood supply similar to humans and have a highly developed immune system, making the tgHD minipig a well-suited model to study the feasibility, efficacy, and tolerability of a microRNA-based huntingtin-lowering gene therapy to better translate preclinical studies to the clinic.

First, the optimal delivery route for transduction of the affected putamen and caudate nucleus in a large animal brain was studied. AAV5 encoding GFP was used. Direct intracranial administration into the striatal complex was found to result in most favorable transduction of the deep brain structures that are affected in HD, and this also covered the relevant frontal cortical structures through axonal transport.

After assessing the route of administration, the efficacy of a therapeutic transgene encoding an engineered miRNA against HTT mRNA (AAV5-miHTT) was investigated in tgHD minipigs. One-time intracranial administration of AAV5-miHTT resulted in widespread vector distribution throughout the tgHD minipig brain that correlated with therapeutic microRNA expression. The efficacy of AAV5-miHTT to lower human mutant huntingtin was demonstrated up to six months after one-time treatment. Human mutant huntingtin mRNA and protein were significantly reduced in all brain regions transduced by AAV5-miHTT. We achieved HTT mRNA lowering of up to 72.8% and human mutant huntingtin protein up to 85.3% in the large HD animal model brain, similar to knockdown levels achieved in smaller HD rodents. The observed strong human mutant huntingtin protein lowering in the striatum of tgHD minipigs provides additional confidence for future applicability of the AAV5-miHTT huntingtin-lowering gene therapy for HD patients.

Although the current study was specifically designed to assess the distribution and efficacy of the huntingtin lowering gene therapy, CSF was sampled to explore a putative inflammatory response to the treatment. Both cytokines and soluble mutant huntingtin levels were slightly elevated in the CSF of tgHD minipigs one week after intracranial administration. As all markers returned to basal levels two weeks after injection, suggesting a transient response to the invasive administration procedure. This was confirmed by histological examination of cortico-striatal brain slices where normal striatal functioning was shown with lack of global microglial expression, providing evidence that intracranial injection of AAV5-miHTT was well tolerated in the tgHD minipigs.

The extensive human mutant huntingtin lowering, widespread distribution, long-term expression and tolerability of AAV5-miHTT, supports further development of the huntingtin-lowering gene therapy and initiation of clinical trials in HD patients in the near future.

  1. Ross, C.A. and Tabrizi, S.J. (2011). Huntington's disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 10, 83-98.
  2. Miniarikova J., Evers M.M. and Konstantinova P. (2018). Translation of MicroRNA-Based Huntingtin-Lowering Therapies from Preclinical Studies to the Clinic. Mol Ther. 26, 947-962.
  3. Wild E.J. and Tabrizi S.J. (2017). Therapies targeting DNA and RNA in Huntington's disease. Lancet Neurol. 16, 837-847.
  4. Miniarikova, J. et al. (2016). Design, Characterization, and Lead Selection of Therapeutic miRNAs Targeting Huntingtin for Development of Gene Therapy for Huntington's Disease. Mol Ther Nucleic Acids. 5, e297.
  5. Miniarikova, J. et al. (2017). AAV5-miHTT gene therapy demonstrates suppression of mutant huntingtin aggregation and neuronal dysfunction in a rat model of Huntington's disease. Gene Ther. 24, 630-639.
  6. Morton, A.J. and Howland, D.S. (2013). Large genetic animal models of Huntington's Disease. J Huntingtons Dis. 2, 3-19. 
  7. Baxa, M. et al. (2013). A transgenic minipig model of Huntington's Disease. J Huntingtons Dis. 2, 47-68.

Society News

ASGCT to Award Up To $245,000 in Support of Students and Trainees

ASGCT recently created 14 new grant opportunities to support members developing their careers. The Society will award up to $175,000 in Career Development Awards and up to $70,000 in Career Travel Awards—applications will be accepted through August 1. For more information on eligibility, applications, deadlines, and required documents, please visit Grants & Awards.

Thoughts on FDA’s Gene Expressions

Dr. Michele Calos, ASGCT  President, spoke with Bloomberg News about the release and impact of the six new FDA guidance documents and the future of gene therapy…Read More

New Molecular Therapy Impact Factors Announced

Molecular Therapy: 7.008 increased by 4.8%
Molecular Therapy – Nucleic Acids: 5.660
Molecular Therapy – Oncolytics: 3.690 (increased by 193% up from 1.259)
Molecular Therapy – Methods & Clinical Development: 3.681 (increased 41% up from 2.61)

Public Policy

ASGCT Submits Comments to CMS on Coverage and Reimbursement of CAR T-Cell Therapies

ASGCT submitted comments last month to the Centers for Medicare & Medicaid Services (CMS) on Medicare coverage and reimbursement of CAR T-cell therapies. United Healthcare recently requested a national coverage analysis (NCA) of CAR T-Cell therapies. When it concludes an NCA, CMS may establish a national coverage determination (NCD) or maintain the status quo, which allows local Medicare administrative contractors to set reimbursement policy.

ASGCT expressed concern over potential limitations to patient access to CAR T-cell therapy for Medicare beneficiaries posed by the CMS NCA, and the potential resulting establishment of an NCD. ASGCT questioned the need for an NCD at this point because CAR T-cell therapies approved by the FDA are currently covered by CMS for medically accepted use consistent with their labeling. Since ongoing clinical trials are likely to identify new patient populations that may benefit from CAR T-cell therapy, another potential problem is that the NCA and a potential NCD may lack sufficient scope or flexibility to allow expeditious patient access to future CAR T-cell indications.

ASGCT also submitted comments to CMS in June regarding how to improve reimbursement of CAR T-cell therapy through the Medicare inpatient prospective payment system (IPPS). The level that Medicare reimburses for CAR T-cell therapy through current mechanisms often leaves a significant gap in payment to PPS hospitals compared to their combined costs for services and for the biologic therapy, creating high risk of substantial financial losses to hospitals for providing the therapy. ASGCT is concerned that such losses may be unsustainable for providers, which could ultimately affect availability of the therapy for patients.

The alternative that ASGCT supported as the most likely to provide the most appropriate reimbursement level would be to pay the drug acquisition cost separately as a pass-through payment (the average sales price), in addition to CMS assignment of CAR T-cell therapy to a higher weighted existing Medicare severity diagnosis-related group (MS-DRG 016, currently used for autologous bone marrow transplant). ASGCT supports the creation of a new DRG for CAR T-cell therapy when sufficient utilization data is available. 

FDA Funding and Communication Is an ASGCT Priority

ASGCT signed on to a letter last month from the Alliance for a Stronger FDA to House and Senate appropriators in support of robust FDA funding in fiscal year 2019. More specifically, organizations supported the $150 million more in increased funding that House appropriators have recommended over the Senate in this appropriations cycle. Increased funding would support areas of high priority for gene and cell therapy—innovation of treatments for rare diseases; expediting the development of treatments (e.g., through the Oncology Center of Excellence and the 21st Century Cures FDA Innovation Account); and increased domestic manufacturing, which may be especially important for gene and cell therapy.

Also in June, Adora Ndu, JD, PharmD, member of the ASGCT Clinical Trials & Regulatory Affairs Committee, represented ASGCT at a meeting hosted by Research America with Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research (CBER). Highlights of Dr. Marks’ comments included that all six draft guidance documents on gene therapy are likely to be issued publicly this summer, including a recently announced guidance on clinical pathways for retinal disorders. He also emphasized the FDA’s important relationship on advanced therapies, such as gene therapy, with their European counterparts—the European Medicines Agency (EMA) and the European Commission (EC). Recent interactions of these groups have indicated willingness to encourage development of common scientific approaches on the regulation of these medicines, which could best facilitate their preclinical and clinical development. At the Research America meeting, Dr. Marks also noted that the newly announced CBER INTERACT (INitial Targeted Engagement for Regulatory Advice on CBER ProducTs) meetings will replace the pre-investigational New Drug (IND) meetings and allow sponsors to get CBER feedback on regulatory expectations earlier in the development process.

ASGCT Supports Discussion of the Role of Gene Editing in National Health Security

ASGCT sent letters of support last month to Senator Tim Scott (R-SC) and Senator Richard Burr (R-NC) for their roles in the inclusion of a relevant provision to the Senate version of the Pandemic and All-Hazards Preparedness and Advancing Innovation Act of 2018 (PAHPA). The provision calls for a meeting within a year from enactment to discuss the potential role that genomic engineering technologies, including gene editing, may have in advancing national health security. Although ASGCT members focus primarily on human therapeutic applications of gene editing, the Society recognizes that this technology has the potential to contribute to additional societal benefits. For example, gene editing could boost the ability to manage disease threats and develop countermeasures to biological weapons. ASGCT acknowledges the need for continuing the conversation on these topics on a national level, and is particularly supportive of the language in the provision that calls for inclusion of representatives from academic, private, and non-profit entities with expertise in genome engineering technologies, biopharmaceuticals, medicine, or bio defense, and other relevant stakeholders in such a meeting. Including scientific researchers in these deliberations is extremely important because they are able to utilize their expertise to assess scientific feasibility of the types of activities that may pose concerns, manage threats, or offer countermeasure solutions.

Upcoming Legislative Briefing on Gene Editing to Educate Medical Technology Caucus

ASGCT will provide a briefing for the Medical Technology Caucus on July 16 on the topic of Gene Editing Technologies: Potential and Policy Implications. The Medical Technology Caucus is a group of 40 members of the House of Representatives that aims to increase congressional awareness of the issues related to medical technology and technological improvements in health care. ASGCT Board member Keith Joung, MD, PhD and ASGCT member John Zaia, MD will educate legislative staff about gene editing and its therapeutic applications. ASGCT Government Relations Committee Chair Tim Hunt, JD, will address how legislators can support the benefits of gene editing and other types of gene therapy through policies that relate to NIH and FDA funding, patient access to approved therapies, and orphan drug development incentives, among others.

Industry News

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