Abstract
The past year has witnessed seismic shifts in many aspects of human endeavor with woman leaders positively impacting government, societal, and academic spheres. In the realm of science, the 2020 Nobel Prize in Chemistry was awarded to Professors Jennifer Doudna, PhD, and Emmanuelle Charpentier, PhD, for their discovery of clustered regularly interspaced short palindromic repeats (CRISPR), which has transformed the landscape of gene therapy forever. This award has further amplified those shock waves, as woman gene therapy scientists see the truly limitless possibilities for the impact of their own careers. In this issue of Human Gene Therapy on the occasion of the 2021 American Society for Gene and Cell Therapy Annual Meeting, we chose to highlight a few of the other outstanding woman scientists in our field whose articles are published here.
The issue features an interview with Hildegard Büning, MD/PhD, and HIV researcher at the German Institute for Infection Research at Hannover Medical School. Dr. Büning has not only been a cutting-edge researcher in the adeno-associated virus (AAV) field, but has also taken on a crucial leadership role as the president of the European Society of Gene and Cell Therapy over the past 3 years. Under Dr. Büning's leadership, the European Society of Gene and Cell Therapy has grown closer to the American Society of Gene and Cell Therapy and has continued to make a tremendous impact in human gene therapy spanning the translational spectrum from basic to clinical research. We are also very grateful to Dr. Büning for her ongoing contributions to Human Gene Therapy as our European Editor.
We are pleased to include a special commentary from Joy Cavagnaro, PhD, a pioneering regulatory scientist in the gene therapy field. Over the past 30 years with the U.S. Food and Drug Administration (FDA) and in industry, Dr. Cavagnaro has gained keen insights into the value that regulatory science plays in the development of safe and effective human gene therapies. Dr. Cavagnaro shares those insights as she has participated in the evolution of the field over those decades and demonstrates how great women in regulatory science have been indispensable to the progression of the gene therapy field.
Next, we feature a review article by Nathalie Cartier, MD/PhD, who is the research director at Institut National de la Santé et de la Recherche Médicale (INSERM) in France, the founder of BrainVectis, and also serves as a senior consulting editor for Human Gene Therapy. Dr. Cartier and her team have contributed a wonderfully comprehensive review of the strategies and tools to achieve efficient delivery of genes to the central nervous system (CNS). One of the most fascinating aspects of gene therapy is the ability to cure diseases that were previously designated as incurable. Many diseases that fall into that category are either genetic, neurologic, or both. Dr. Cartier's review provides a crucial update of the progress that has been made in the field of CNS gene therapy over the past 10 years. These efforts have slowly but surely begun to fulfill the promise that many patients and families have sought.
Louise Rodino-Klapac, PhD, of Sarepta Therapeutics and her colleagues have contributed two important original research articles to this issue, one addressing Duchenne muscular dystrophy (DMD) and the other addressing limb girdle muscular dystrophy type 2D (LGMD2D). In the DMD study, Dr. Rodino-Klapac demonstrates a proof of concept in which dose escalation of systemic delivery of an rAAVrh74 vector expressing a microdystrophin gene from the muscle cardiac-specific promoter MHCK7 in mdx mice was able to mediate significant improvements in muscle strength at higher doses of vector (1.2 × 1013 vg/kg or 6 × 1014 vg/kg). This vector appears to be an important clinical candidate for a disease that currently does not have an approved gene therapy.
Dr. Rodino-Klapac was also the lead on an article describing a preclinical study on systemic delivery of a self-complementary AAVrh74 vector expressing alpha sarcoglycan in Sgca-/- mice. As with DMD, the LGMD2D studies led by Dr. Rodino-Klapac are leading the way to future clinical application for a disease that is currently not treatable with any specific therapy. The process of translating gene therapy technology to address the unique clinical needs of specific patient populations represents the essence of human gene therapy as a field and the mission of Human Gene Therapy as a journal.
Continuing on the theme of gene therapy for single gene disorders, Drs. Jennifer Saville and Maria Fuller from the Department of Genetics and Molecular Pathology at Women's and Children's Hospital and the University of Adelaide, South Australia, have contributed an important proof-of-concept study on systemic delivery of a self-complementary rAAV9 vector expressing N-sulfoglucosamine sulfohydrolase (SGSH) in a mouse model of mucopolysaccharidosis Type IIIA. In this case, the primary target was the CNS and the team has demonstrated both evidence of gene transfer and of partial functional correction in the mouse model. As a result, several key indicators of functional recovery were observed to return to nearly normal levels. However, in older mice, neurocognitive impairment persisted despite clearance of the storage product (gangliosides). These studies point out important limitations to gene therapy when administered after certain critical periods of neurodevelopment.
Mai ElMallah, MD, and her collaborators at Duke University present an important initial proof-of-concept study of rAAV-mediated gene therapy in a mouse model of alternating hemiplegia of childhood, a monogenic disorder caused by mutations in the ATP1A3 gene. This devastating neurologic disorder causes disabling episodes of hemiplegia, ataxia, severe developmental impairments, and death. In this case, the team used an rAAV9 vector expressing ATP1A3 delivered by a combination of intracisternal magna and bilateral intracerebral ventricle injection to mice, which subsequently demonstrated a variety of important functional improvements, providing a hopeful demonstration of the potential of this treatment.
Gloria Gonzalez-Aseguinolaza, PhD, of the Navarra Institute for Health Research in Pamplona, Spain, and her collaborators have also provided hope to a previously incurable condition, in this case hepatitis B virus (HBV) infection, the most common cause of end-stage liver disease and cancer worldwide with an annual death toll of ∼1 million people per year. The ingenious approach they have developed will limit gene expression by harnessing therapeutic interferon alpha expression to the noncanonical splicing of the X-box binding protein-1 (XBP-1), a gene that is dramatically induced in HBV-infected cells. Directed applications of gene therapy to prevalent disorders such as HBV infection are an important aspect of gene therapy's future.
One of the points we hope to convey in this special issue is that women scientists are leading in gene therapy. From high-profile discoveries such as the Doudna–Charpentier Nobel Prize worthy CRISPR discovery or the pioneering study on the crystal structure of DNA that earned Rosalind Franklin, PhD, her rightful place in the pantheon of science, women in gene therapy are providing hope through pivotal proof of concept and clinical studies of previously incurable disorders. The gene therapy field would do well to channel the passion that the researchers featured in this issue have shown in making their science felt with this level of crucial human impact.
Tragically, this special issue will be published shortly after the passing of one of the most remarkable woman scientists in the field of gene therapy, Mavis Agbandje-McKenna, PhD, who died on March 2, 2021. Dr. Agbandje-McKenna's career journey was highlighted in an interview she gave to our Executive Editor, Dr. Kevin Davies, which was published in Human Gene Therapy in June of 2020. 1 Dr. Agbandje-McKenna made tremendous contributions to the understanding of the structural biology of AAV, which is currently the most commonly used in vivo gene therapy vector. The hallmark of Dr. Agbandje-McKenna's scientific career was collaboration, and in this issue we have assembled tributes from many of her co-authors and collaborators. As these tributes illustrate, she will be keenly missed.