Abstract
Ronald G. Crystal, M.D., of the Department of Genetic Medicine at Weill Cornell Medical College, notes that whereas rare-disease researchers know they must carry out safety studies on their vectors in animals before inserting the vectors into humans, their opinions are divided on how to collect the resulting data: Should researchers pool results from past studies? Or allow access to their data? It's difficult to get that safety data published, he said, because journals typically shy away from results that don't address a hypothesis or arouse academic interest through clever answers to vexing problems; and yet safety data are critical to the clinical development of drugs. Such publication would yield a second positive benefit—recognition for researchers and postdocs, who often find it difficult to get their safety studies published.
“Let's say you're an investigator, and you use AAV5, and you do a whole bunch of safety studies. I could quote that in my application to the FDA as an example of safety. It doesn't mean I could get away with doing no work, but it would certainly reduce my burden, and reduce the burden in the field of the repetitive work we all do, because nobody knows what everybody else has done. Nor does the FDA,” Dr. Crystal said in an interview.
“That's the idea—everybody wins. It's a way of getting information out. It's a journal focused on this. It's an area of science that is not really hypothesis-driven. It's not exciting new generation of knowledge. But it's critical knowledge for the development of drugs,” Dr. Crystal added. “By doing this, I think we'll be able to get recognition to the people doing it, the investigators and the postdocs, but also be able to move the field along. People will then have the information that will help them in designing their trials, and getting their vectors into humans.”
Dr. Crystal was among panelists at the Gene Transfer and Rare Diseases Workshop, held September 13, 2012, by the NIH in Rockville, Maryland, who addressed whether common studies or assays can be shared across different trials involving similar diseases or vectors, as well as what factors the studies should have in common for the shared data to be useful.
The NIH organized and sponsored the workshop as a joint effort of its Office of Biotechnology Activities (OBA), Office of Science Policy, Office of the Director, Office of Rare Diseases Research (ORDR), and the National Center for Advancing Translational Sciences (NCATS).
Panelists agreed that a journal dedicated to reviewing and publishing such studies would serve a valuable function in advancing data-sharing by researchers. Plans for such a publication were announced at the workshop by HGT Editor-in-Chief James M. Wilson, M.D., Ph.D.
Dr. Wilson will serve as editor-in-chief of Human Gene Therapy Clinical Development, while Barry J. Byrne, M.D., Ph.D., of the University of Florida, will be the journal's clinical development editor. Human Gene Therapy Clinical Development is planned for launch at the beginning of 2013.
“We want to be able to publish papers, clinical trials, that aren't groundbreaking enough to really make it through peer review in higher visibility journals. This comes from the concern of many stakeholders that negative clinical trials are very important in informing about medicine and therapeutics, but they're never published because they're negative. So Human Gene Therapy Clinical Development will publish these preclinical safety studies, and any clinical trial, even if it didn't succeed. We're also going to publish clinical protocols independent of the data, if they're really cutting edge and first-in-human.”
“Researchers using a particular technology platform,” he said, “should find value from studies published by another user of that platform with information on how to set up and, how to proceed, let alone the clinical data that platform is designed to help produce.”
“The data submitted to the FDA and EMA are by law confidential. The regulators can't distribute those data. But the investigators can. So we, as a community in gene therapy, think it would be very useful if a lot of the data that's submitted to support INDs or clinical trials was made publicly available,” Dr. Wilson said. “They may lead to the opportunity to do fewer safety studies if you could reference the work with the other member of the platform. And for orphan diseases, in which we're really resource constrained, that would be very, very helpful.”
Guidances under development by the CPWP or GTWP have been taken over by the drafting groups, which will include about five experts drawn from the CAT membership and the EMA European expert list (
The EMA said the change was intended to strengthen CAT's role as the agency's reference body dealing with all aspects of developing advanced-therapy medicines in Europe. The EMA also justified the move as part of an effort to make best use of its available expertise and improve the efficiency of its operations.
The CPWP and GTWP both predate the creation of the CAT in 2009, when the working parties were transferred within the EMA from the Committee for Medicinal Products for Human Use (CHMP).
The GTRP provides investigators with select gene vector manufacturing services, pharmacology/toxicology testing services, regulatory affairs assistance, and partial funding for conducting clinical trials. The GTRP also provides consulting in preclinical gene vector type selection and study design, pharmacology/toxicology study design, and clinical study design.
The GTRP provides services at no cost to investigators. Although the GTRP primarily exists to support the translational work of NHLBI-funded gene therapy investigators, investigators funded by other NIH institutes, centers, or programs may also collaborate with the resource program.
As with the original program, the renewed GTRP has five components, listed below with their overseers: • Preclinical Vector Production Core Laboratory, based at the University of Pennsylvania's Penn Vector Core lab; HGT editor James M. Wilson, M.D., Ph.D. • Clinical Coordinating Center at Social & Scientific Systems, Inc.; Susan Sepelak, M.S., M.S.M. • Clinical-grade Lentivirus Vector Production Core Laboratory at Indiana University Vector Production Facility; Kenneth Cornetta, M.D. • Pharmacology/Toxicology Core Laboratory at Lovelace Biomedical and Environmental Research Institute; Janet Benson, Ph.D. • Clinical-grade adeno-associated virus (AAV) Vector Production Core Laboratory at the Children's Hospital of Philadelphia; J. Fraser Wright, Ph.D.
The formal termination of the Ebola program follows a stop-work order issued by the DoD to the company on August 2, running through the termination, while JPM-TMT evaluated the Ebola medical countermeasure development efforts of Sarepta and another company, Tekmira Pharmaceuticals (
Sarepta said it has entered into settlement talks with DoD regarding costs associated with the termination. Under a settlement agreement, the government may reinstate the Ebola portion of Sarepta's contract if the company's Ebola therapeutic “becomes the only alternative under which the government can fulfill its requirement because the other company fails in developing its Ebola therapeutic or is in default of contract requirements,” the company said—provided that the Marburg program continues to operate at that time, or if DoD subsequently identifies additional funding for both Ebola medical countermeasure efforts to continue.
Sarepta received the proverbial back of the hand from the DoD about a month after receiving a pat on the back from another federal agency. On September 18, the company announced the FDA's approval of Fast Track status for lead infectious drug candidates stemming from both programs—AVI-7288 for Marburg virus and AVI-7537 for Ebola. At the time, Sarepta said it was evaluating the safety and efficacy of AVI-7288 for the treatment of Marburg virus following FDA's Animal Rule, applied to drugs for life-threatening agents where ethics or feasibility preclude human efficacy trials, and was planning to initiate a phase 1 multiple ascending dose study to characterize the safety, tolerability, and pharmacokinetics of AVI-7288 after repeat dosing in healthy adult volunteers.
Earlier this year, both Sarepta and Tekmira reported that their treatments demonstrated success against Ebola. Tekmira said its treatment protected macaques from Zaire Ebola, a strain of the virus that kills up to 9 of 10 people infected, while Sarepta disclosed data from a confirmatory study demonstrating survival of 75% of nonhuman primates administered AVI-7537, compared with 0% in a placebo group.
The 3-day therapy restored the protein IFT88 back into the olfactory neurons, giving cells the ability to regrow and extend cilia off the dendrite knob, which is needed by the olfactory neurons to detect odors. Only 14 days after treatment, the mice had a 60% increase in body weight, suggesting they responded by eating more. Neurons involved in smelling were seen to be functioning correctly after the mice were exposed to strong-smelling amyl acetate, also called banana oil.
In their study published in Nature Medicine, the research team reported their progress in reversing congenital anosmia, and said their work may also aid research on other conditions stemming from cilia problems. The team cautioned, however, that more time will be needed before their work affects human treatment, and that the people most likely to benefit are those who lose their sense of smell because of genetic factors rather than through aging, head trauma, or chronic sinus problems.
“Essentially, we induced the neurons that transmit the sense of smell to regrow the cilia they'd lost,” the study's corresponding author, Jeffrey R. Martens of the University of Michigan, Ann Arbor, said in a statement.
Dr. Martens said he and his team will continue to look for other cilia-related genetic causes of anosmia, including nonlethal causes of the disorder in humans: “We hope this stimulates the olfactory research community to look at anosmia caused by other factors, such as head trauma and degenerative diseases,” he said. “We know a lot about how this system works—now [we] have to look at how to fix it when it malfunctions.”
[McIntyre, J.C., Davis, E.E., Joiner, A., Williams, C.L., Tsai, I., Jenkins, P.M., McEwen, D.P., Zhang, L., Escobado, J., Thomas, S., Szymanska, K., Johnson, C.A., Beales, P.L., Green, E.D., Mullikin, J.C., NISC Comparative Sequencing Program, Sabo, A., Muzny, D.M., Gibbs, R.A., Attie-Bitach, T., Yoder, B.K., Reed, R.R., Katsania, N., Martens, J.R. (2012). Gene therapy rescues cilia defects and restores olfactory function in a mammalian ciliopathy model. Nat. Med. 18, 1423–1428.]
Research teams led by Fabio Candotti, M.D., a senior author and senior investigator in the Genetics and Molecular Biology Branch of the NIH National Human Genome Research Institute (NHGRI;
Results of the trial were recently published in Blood, the journal of the American Society of Hematology.
Four of the young patients remained on enzyme replacement therapy throughout the procedure. They experienced no adverse effects, but did not gain ADA function. The authors suggested that the enzyme replacement therapy may have diminished the treatment's effect by diluting the number of corrected lymphocytes in the children's immune systems.
For six additional young patients, the doctors stopped enzyme replacement therapy and treating them instead with a low dose of a chemotherapy that depletes stem cells in the bone marrow, making space for the gene-corrected stem cells that had been given the new gene in the laboratory and then returned to each patient's body. The lower dose resulted in enhanced efficacy for the corrected stem cells, researchers found.
“Not only have we realized an important advancement in gene therapy, but we have seen a renewal of health in our patients,” Dr. Candotti said in a statement. “We are encouraged by the outcome of our gene therapy trial.”
An additional eight children, most 1 year old or younger, have been added to a second phase of the study. The younger patients are showing even more favorable response rates to the therapy, Dr. Candotti said.
[Candotti, F., Shaw, K.L., Muul, L., Carbonaro, D., Sokolic, R., Choi, C., Schurman, S.H., Garabedian, E., Kesserwan, C., Jagadeesh, G.J., Fu, P., Gschweng, E., Cooper, A., Tisdale, J.F., Weinberg, K.I., Crooks, G.M., Kapoor, N., Shah, A., Abdel-Azim, H., Yu, X., Smogorzewska, M., Wayne, A.S., Rosenblatt H.M., Davis, C.M., Hanson, C., Rishi, R.G., Wang, X., Gjertson, D., Yang, O.O., Balamurugan, A., Bauer, G., Ireland, J.A., Engel, B.C., Podsakoff, G.M., Hershfield, M.S., Blaese, R.M., Parkman, R., and Kohn, D.B. (2012). Gene therapy for adenosine deaminase-deficient severe combined immune deficiency: Clinical comparison of retroviral vectors and treatment plans. Blood 02-400937.]
The discovery could create another avenue for producing the insulin needed by people with diabetes, given the difficulty of carrying out traditional islet transplantation because of the traditional shortage of organ donors. SeV vectors, according to the researchers, are superior to conventional viral vectors because they do not go through a DNA phase and can introduce foreign genes without toxicity into a variety of cell types.
The four transcription factors examined were Pdx-1 (pancreatic and duodenal homeobox-1), NeuroD (neurogenic differentiation), MafA (musculoaponeurotic fibrosarcoma oncogene A), and Ngn (neurogenin). Of all of the different combinations examined, the combination of Pdx-1, NeuroD, and MafA was the most effective for the expression of insulin-2 mRNA, researchers said.
In addition, they said, expression of insulin-2 mRNA could be detected after transduction with combinations of three or more transcription factors, using SeV vectors. When combinations of two transcription factors were transduced, using the SeV vector—including Pdx-1 plus NeuroD, Pdx-1 plus MafA, and NeuroD plus MafA, the expression of insulin-2 mRNA was low but could be detected. mPSCs transduced with single transcription factors, using SeV vectors, could not express the insulin-2 mRNA.
“These data suggest that the transduction of transcription factors, using SeV vectors, facilitates mPSC differentiation into insulin-producing cells and showed the possibility of regenerating beta cells by using transduced PSCs,” the researchers concluded.
[Yukawa, H., Noguchi, H., Oishi, K., Miyamoto, Y., Inoue, M., Hasegawa, M., Hayashi, S., Baba, Y. (2012). Differentiation of mouse pancreatic stem cells into insulin-producing cells by recombinant Sendai virus-mediated gene transfer technology. Cell Med. 3, 51-61—Alex Philippidis.]