How novel antibody suppresses HIV for four months, by research
*Gene therapy restores immunity in infants with rare immunodeficiency disease
*Team uses material editing with CRISPR to treat lethal lung infections before birth
Regular infusions of an antibody that blocks the Human Immuno-deficiency Virus (HIV) binding site on human immune cells may have suppressed levels of HIV for up to four months in people undergoing a short-term pause in their antiretroviral therapy (ART) regimens, according to a report published online in The New England Journal of Medicine.
A result of the Phase 2, open-label study indicate the antibody, known as UB-421, was safe and did not induce the production of antibody-resistant HIV. The study was supported in part by the National Institute of Allergy and Infectious Diseases (NIAID), a component of the National Institutes of Health, and United Biopharma, Inc.
The study was conducted in Taiwan and led by Chang Yi Wang, Ph.D., Chief Scientific Officer and Chairperson of United BioPharma, Inc. Twenty-nine volunteers with well-controlled HIV discontinued their normal regimens of daily oral ART at the time of their first infusion or one week later, depending on their Anti Retroviral Therapy (ART) regimen. Fourteen study participants received eight regular weekly infusions of UB-421, while 15 received eight higher-dose infusions every other week. At the end of the eight- or 16-week treatment period, all volunteers restarted their previous ART regimen and were evaluated in follow-up visits up to eight weeks later. Apart from a single participant who discontinued the study because of a mild skin rash, volunteers in both groups maintained HIV suppression (plasma HIV RNA levels under 20 copies/mL) throughout the treatment period in the absence of ART.
Previous experimental infusions of broadly neutralizing antibodies, or bNAbs, have suppressed HIV for about two weeks by targeting proteins on the virus itself, but the rapid mutation rate of HIV induces antibody-resistant strains that render the treatment ineffective. UB-421 theoretically avoids this possibility by blocking a stable human protein that HIV uses to infect T cells. Indeed, resistance to UB-421 was not seen in this study. Because the small study did not include a comparator group receiving a placebo infusion, further studies have been planned in Taiwan and Thailand to evaluate the safety and efficacy of UB-421 as a treatment for HIV. In a related study, NIAID investigators currently are evaluating the safety of regular infusions of two highly potent bNAbs that may prevent the development of resistant HIV strains by targeting two distinct areas of the virus.
Meanwhile, a small clinical trial has shown that gene therapy can safely correct the immune systems of infants newly diagnosed with a rare, life-threatening inherited disorder in which infection-fighting immune cells do not develop or function normally. Eight infants with the disorder, called X-linked severe combined immunodeficiency (X-SCID), received an experimental gene therapy co-developed by National Institutes of Health scientists. They experienced substantial improvements in immune system function and were growing normally up to two years after treatment. The new approach appears safer and more effective than previously tested gene-therapy strategies for X-SCID.
These interim results from the clinical trial, supported in part by United States National Institute for Health (NIH), were published in The New England Journal of Medicine.
Infants with X-SCID, caused by mutations in the IL2RG gene, are highly susceptible to severe infections. If untreated, the disease is fatal, usually within the first year or two of life. Infants with X-SCID typically are treated with transplants of blood-forming stem cells, ideally from a genetically matched sibling. However, less than 20 percent of infants with the disease have such a donor. Those without a matched sibling typically receive transplants from a parent or other donor, which are lifesaving, but often only partially restore immunity. These patients require lifelong treatment and may continue to experience complex medical problems, including chronic infections.
“A diagnosis of X-linked severe combined immunodeficiency can be traumatic for families,” said Anthony S. Fauci, M.D., director of NIH’s National Institute of Allergy and Infectious Diseases (NIAID). “These exciting new results suggest that gene therapy may be an effective treatment option for infants with this extremely serious condition, particularly those who lack an optimal donor for stem cell transplant. This advance offers them the hope of developing a wholly functional immune system and the chance to live a full, healthy life.”
Also, using CRISPR gene editing, a team from Children’s Hospital of Philadelphia (CHOP) and Penn Medicine have thwarted a lethal lung disease in an animal model in which a harmful mutation causes death within hours after birth. This proof-of-concept study, published in Science Translational Medicine, showed that in utero editing could be a promising new approach for treating lung diseases before birth.
“The developing fetus has many innate properties that make it an attractive recipient for therapeutic gene editing,” said study co-leader William H. Peranteau, MD, an investigator at CHOP’s Center for Fetal Research, and a pediatric and fetal surgeon in CHOP’s Center for Fetal Diagnosis and Treatment. “Furthermore, the ability to cure or mitigate a disease via gene editing in mid- to late gestation before birth and the onset of irreversible pathology is very exciting. This is particularly true for diseases that affect the lungs, whose function becomes dramatically more important at the time of birth.”
The lung conditions the team is hoping to solve — congenital diseases such as surfactant protein deficiency, cystic fibrosis, and alpha-1 antitrypsin — are characterized by respiratory failure at birth or chronic lung disease with few options for therapies. About 22 percent of all pediatric hospital admissions are because of respiratory disorders, and congenital causes of respiratory diseases are often lethal, despite advances in care and a deeper understanding of their molecular causes. Because the lung is a barrier organ in direct contact with the outside environment, targeted delivery to correct defective genes is an attractive therapy.
“We wanted to know if this could work at all,” said study co-leader Edward E. Morrisey, PhD, a professor of Cardiovascular Medicine in the Perelman School of Medicine at the University of Pennsylvania. “The trick was how to direct the gene-editing machinery to target cells that line the airways of the lungs.”
The researchers showed that precisely timed in utero delivery of CRISPR gene-editing reagents to the amniotic fluid during fetal development resulted in targeted changes in the lungs of mice. They introduced the gene editors into developing mice four days before birth, which is analogous to the third trimester in humans.
The cells that showed the highest percentage of editing were alveolar epithelial cells and airway secretory cells lining lung airways. In 2018, a team led by Morrisey identified the alveolar epithelial progenitor (AEP) lineage, which is embedded in a larger population of cells called alveolar type 2 cells. These cells generate pulmonary surfactant, which reduces surface tension in the lungs and keeps them from collapsing with every breath. AEPs are a stable cell type in the lung and turn over very slowly, but replicate rapidly after injury to regenerate the lining of the alveoli and restore gas exchange.
In a second experiment, the researchers used prenatal gene-editing to reduce the severity of an interstitial lung disease, surfactant protein C (SFTPC) deficiency, in a mouse model that has a common disease-causing mutation found in the human SFTPC gene. One hundred percent of untreated mice with this mutation die from respiratory failure within hours of birth. In contrast, prenatal gene editing to inactivate the mutant Sftpc gene resulted in improved lung morphology and survival of over 22 percent of the animals.
Meanwhile, to restore immune function to those with X-SCID, scientists at NIAID and St. Jude Children’s Research Hospital in Memphis, Tennessee, developed an experimental gene therapy that involves inserting a normal copy of the IL2RG gene into the patient’s own blood-forming stem cells. The Phase 1/2 trial reported today enrolled eight infants aged 2 to 14 months who were newly diagnosed with X-SCID and lacked a genetically matched sibling donor. The study was conducted at St. Jude and the Benioff Children’s Hospital of the University of California, San Francisco. Encouraging early results from a separate NIAID-led study at the NIH Clinical Center informed the design of the study in infants. The NIH study is evaluating the gene therapy in older children and young adults with X-SCID who previously had received stem cell transplants.
The gene therapy approach involves first obtaining blood-forming stem cells from a patient’s bone marrow. Then, an engineered lentivirus that cannot cause illness is used as a carrier, or “vector,” to deliver the normal IL2RG gene to the cells. Finally, the stem cells are infused back into the patient, who has received a low dose of the chemotherapy medication busulfan to help the genetically corrected stem cells establish themselves in the bone marrow and begin producing new blood cells.
Normal numbers of multiple types of immune cells, including T cells, B cells and natural killer (NK) cells, developed within three to four months after gene therapy in seven of the eight infants. While the eighth participant initially had low numbers of T cells, the numbers greatly increased following a second infusion of the genetically modified stem cells. Viral and bacterial infections that participants had prior to treatment resolved afterwards. The experimental gene therapy was safe overall, according to the researchers, although some participants experienced expected side effects such as a low platelet count following chemotherapy.
“The broad scope of immune function that our gene therapy approach has restored to infants with X-SCID — as well as to older children and young adults in our study at NIH — is unprecedented,” said Harry Malech, M.D., chief of the Genetic Immunotherapy Section in NIAID’s Laboratory of Clinical Immunology and Microbiology. Dr. Malech co-led the development of the lentiviral gene therapy approach with St. Jude’s Brian Sorrentino, M.D., who died in late 2018. “These encouraging results would not have been possible without the efforts of my good friend and collaborator, the late Brian Sorrentino, who was instrumental in developing this treatment and bringing it into clinical trials,” said Dr. Malech.
Compared with previously tested gene-therapy strategies for X-SCID, which used other vectors and chemotherapy regimens, the current approach appears safer and more effective. In these earlier studies, gene therapy restored T cell function but did not fully restore the function of other key immune cells, including B cells and NK cells. In the current study, not only did participants develop NK cells and B cells, but also four infants were able to discontinue treatment with intravenous immunoglobulins — infusions of antibodies to boost immunity. Three of the four developed antibody responses to childhood vaccinations — an indication of robust B-cell function.
Moreover, some participants in certain early gene therapy studies later developed leukemia, which scientists suspect was because the vector activated genes that control cell growth. The lentiviral vector used in the study reported today is designed to avoid this outcome.
Researchers are continuing to monitor the infants who received the lentiviral gene therapy to evaluate the durability of immune reconstitution and assess potential long-term side effects of the treatment. They also are enrolling additional infants into the trial. The companion NIH trial evaluating the gene therapy in older children and young adults also is continuing to enroll participants.
The gene therapy trial in infants is funded by the American Lebanese Syrian Associated Charities (ALSAC), and by grants from the California Institute of Regenerative Medicine and the National Heart, Lung, and Blood Institute, part of NIH, under award number HL053749. The work also is supported by NIAID under award numbers AI00988 and AI082973, and by the Assisi Foundation of Memphis. More information about the trial in infants is available on ClinicalTrials.gov using identifier NCT01512888. More information about the companion trial evaluating the treatment in older children and young adults is available using ClinicalTrials.gov identifier NCT01306019.
Meanwhile, future studies will be directed towards increasing the efficiency of the gene editing in the epithelial lining of lungs as well as evaluating different mechanisms to deliver gene-editing technology to lungs. “Different gene editing techniques are also being explored that may one day be able to correct the exact mutations observed in genetic lung diseases in infants,” Morrisey said.
Morrisey collaborated on a recent study led by Peranteau and Kiran Musunuru, MD, PhD, an associate professor of Cardiovascular Medicine at Penn, demonstrating the feasibility of in utero gene editing to rescue a lethal metabolic liver disease in a mouse model — the first time in utero CRISPR-mediated gene editing prevented a lethal metabolic disorder in animals. Similar to that study, Peranteau says, “The current research is a proof-of-concept study highlighting the exciting future prospects for prenatal treatments including gene editing and replacement gene therapy for the treatment of congenital diseases.”
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