Abstract
T
The most-cited paper of the year appeared in the March issue. Hinderer et al., from the laboratory of James M. Wilson at the University of Pennsylvania, shook the field with a report of severe hepatotoxicity in nonhuman primates (NHPs) after intravenous (i.v.) injection of a dose of 2 × 1014 vg/kg of a recombinant adeno-associated virus serotype 9 (rAAV9)-like vector (AAVhu68) designed to treat spinal muscular atrophy (SMA), along with subclinical pathology in the dorsal root ganglia (DRG) in these animals. 1 The liver toxicity was quite different from that previously described in clinical trials in that it occurred substantially sooner after vector administration than had been observed previously, and was not associated with pre-existing T-cell reactivity to AAV. That paper also described toxicity from rAAVhu68 in piglets, not in the liver but in the DRG, and in this case with a symptomatic sensorineural syndrome. While it is not certain that these toxicities have a human correlate, it is notable that Solid Bioscience's trial of i.v. rAAV9 was temporarily placed on clinical hold by the U.S. Food and Drug Administration (FDA) because of hepatotoxicity a short time later. The rapid dissemination of the preclinical data by this journal exemplifies one of our most important functions within the broader community, namely to be a vehicle for such exchanges, thereby to maximize the safety of clinical trials and accelerate the rate of progress in our field.
The second most-cited paper from Human Gene Therapy in 2018 was the report by Yu et al., from the Guangzhou Institute of Biomedicine and Health, the Chinese Academy of Sciences in Guangzhou, the First Affiliated Hospital of Shenzhen University, and the First Affiliated Hospital of Sun Yat-Sen University. 2 This paper describes the use of CRISPR/Cas9 to create a double knockout of CXCR4 and CCR5 in CD4+ cells, including both the GHOST(3) cell line and primary CD4+ T cells ex vivo. This manipulation rendered the treated cells human immunodeficiency virus (HIV)-resistant, thus providing a potential approach to prevention or therapy in HIV-exposed or -infected individuals. The rapid dissemination of CRISPR-Cas9 gene editing seems likely to be successful, particularly with ex vivo T-cell manipulation. Interestingly, this article from a group of leading laboratories in Southeast China was published 1 month prior to our Special Issue in February 2018 highlighting major advances in gene therapy in the world's most populous country. 3
Another highly cited paper from 2018 was the latest installment in our Target Organ Series. Christopher Evans, Steven Ghivizzani, and Paul Robbins collaborated on superb review of gene therapy for arthritis. 4 Considering the extremely high prevalence of both rheumatoid arthritis (RA) and osteoarthritis (OA), and the demographic aging of the world population, these diseases of the joints are likely to represent important targets for gene therapy going forward. In this review, the authors described a variety of in vivo and ex vivo approaches using rAAV or lentivirus vectors. A number of clinical trials of gene therapy for RA and OA were described, and the potential for approved products for these diseases were discussed.
The Wilson laboratory also contributed the fourth most-cited paper of the year. In that study, Hinderer et al. compared a number of different methods of delivery of rAAV9 vectors designed to treat mucopolysaccharidosis type I or type VII (MPS-I and MPS-VII) in the central nervous system via infusion into the cerebrospinal fluid (CSF). 5 CSF infusion has been done in previous studies using intra-cisternal, intracerebral ventricle (ICV), and intrathecal (IT) infusion. All three methods were compared in large-animal studies in dogs and NHPs. Furthermore, the authors investigated the effects of Trendelenburg positioning on the effectiveness of IT delivery in NHPs. In these studies, the investigators demonstrated that all methods were feasible, but some important differences were observed. The ICV method in dogs was associated with inflammatory toxicity not seen with the other methods. Finally, the study on positioning in the NHPs indicated no particular advantage from Trendelenburg positioning. These studies provide important data to inform the design of clinical trials as rAAV delivery through the CSF continues to advance.
Rounding out the top five papers of the year was a study from the laboratories of Hemant Khanna and Guangping Gao at the University of Massachusetts Medical School. In this study, the investigators developed and tested a minigene version of the cilia-centrosomal protein, CEP290, as a gene therapy for one particular variant of Leber congenital amaurosis (LCA). The landmark success of the U.S. FDA approval of voretigene tiparvovec for RPE65-related inherited retinal dystrophy has led to tremendous optimism regarding the ability to use rAAV vectors as a platform to treat other single gene disorders of the retina. In the case of CEP290, the length of the coding sequence has precluded the simple translation of this concept. The Khanna laboratory has developed a CEP290 minigene construct, encoding amino acid residues 580–1,180 of the CEP290 protein. This construct was shown to restore cilia length in CEP290-deficient cells in cell culture. The construct was then packaged into AAV8 capsids and used for proof-of-concept studies in CEP290-deficient mice. These studies showed partial correction of visual function, which waned to some extent over time. The continued adaptation of this platform to disorders such as CEP290 deficiency demonstrates both the versatility of this platform and the determination that investigators and patient advocacy groups have to utilize this technology to benefit as many patients with rare genetic conditions as possible.
Overall, the past year has witnessed a flurry of clinical and late-stage preclinical activity in the field of gene therapy. Human Gene Therapy continues to be a vitally important publication for the rapid exchange of data regarding the safety and efficacy of gene therapy technology. The journal continues to aspire to fulfill this important mission and thus to hasten the realization of gene therapy's benefits to patients with a wide range of genetic and acquired disorders, including the specific disorders mentioned in these papers: SMA, HIV infection, RA, OA, MPS-I, MPS-VII, and LCA. We look forward to another productive year ahead as the field continues to progress at a very rapid rate.