Cell & Gene Therapy
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Daniel Klein
Lentiviral Vector Gene Therapy: Evolving and Succeeding
HIV-derived lentiviral vectors make for efficient gene therapies
Lentivirus is an incredibly effective genetic manipulator — an aspect it shares with other viruses. After binding to the host cell, the lentivirus’s single-stranded viral RNA undergoes transcription and reintegration, writing its viral RNA into the DNA of the host cell. Now permanently altered, the cell starts making viruses as part of its DNA expression. Under the right circumstances, this ability can be a boon.
One high-profile success story has been Emily Whitehead, whose leukemia was pushed into remission after doctors at Children’s Hospital of Pennsylvania used a CAR-T cell therapy where a lentivirus was used to reprogram her immune cells. Emily, who was 7 when she received the breakthrough therapy, is now 17 and approaching her senior year of high school. HIV’s ability to modify cells has made it the target of many researchers and pharmaceutical developers.
Lentiviral vector gene therapies advancing in the clinic
Dr. Essra Ridha, the chief medical officer of the Cambridge-based gene therapy company AVROBIO, is one such developer. Their focus is on a small subset of lysosomal disorders —Gaucher disease, Cystinosis, and Hunter Syndrome — and have several lentiviral gene therapies currently in development and undergoing Phase 1/2 clinical trials . These lentiviral vector gene therapies have the potential to treat the underlying cause of the disease by modifying hematopoietic stem cells—immature cells that can develop into all types of blood cells—to expressing the missing proteins. Using lentiviral vectors makes this possibility tangible, a fact that Ridha and her team are quite excited by. “By conducting our genetic modification ex vivo, we are able to return the patient their own autologous stem cells,” says Ridha. “It’s excellent because we don't expect people to have immune responses against their own stem cells.”
Managing the immune response to the viral vector is an enormous challenge in cell and gene therapy, a sufficiently strong reaction can make the treatment undeliverable, as can be the case with adeno-associated viruses . This problem is completely sidestepped by focusing the treatment on extracted cells, with attendant benefits of being able to have much greater control over their modification. The result is that no patients need to be excluded; everyone who needs the treatment can get it. “There’s no immune response. It’s a non-issue,” says Ridha. The virus is removed before the cells are returned, ensuring no virus ever enters the patient.
Focusing the treatment on hematopoietic stem cells — blood stem cells — means that a successful therapy is a lifelong solution. After the modified cells engraft into the bone marrow, they will continue to grow and divide, giving rise to many different types of blood and immune cells — each with a copy of the functional gene. “Because these cells in the bone marrow constantly produce circulating cells [expressing the therapeutic protein],” says Ridha, “what you have is essentially a durable therapy that continues working over the lifetime of the patient.” Another factor is that the genetically modified HSC cell in the blood divide and differentiate, passing the inserted DNA on to daughter cells, which then maintain expression of the therapeutic protein and deliver the protein.
Tony Hitchcock, the Technical Director of Charles River Laboratories’ Keele site, which specializes in cell and gene therapy manufacturing, has a more concrete focus: “[Lentiviral vector gene therapies] can be more readily commercially produced… People are developing technologies where they have stable cell lines making these vectors, so that simplifies scale up.” Though there are still manufacturing challenges with lentiviral vectors for gene therapies, its cost gives it a distinct edge over other options. “AAVs [adeno-associated viruses] get a lot of publicity because people have gone to big scales, up to 2000 liters, which sounds great, but it's very expensive to do, whereas [lentivirus] is made at a 10th of that scale.”
Improved safety of lentiviral vector gene therapies
There is natural hesitation and concern for safety, upon hearing that the vector is derived from a virus as dangerous as HIV. Fortunately, much has been done with regards to the risk factors. “What they've been able to do is increase the safety of [lentiviruses] in the way they make it, how they reduce biological risks. So, the actual levels of biological containment needed to produce it have decreased, which makes it easier and safer to use, not only for production companies and facilities like our own, but also clinical centers,” says Hitchcock.
However, the potential benefits of the treatment are undeniable and early trials are ongoing; hundreds of people have already been treated. “The reason is if you treat this sort of disease early enough,” says Ridha, “you can prevent disease from appearing. In some cases, you can reverse some of the features of genetic diseases.” Right now, for so many of these diseases, there’s nothing doctors can do except treat the symptoms. With gene therapy using lentiviral vectors, explains Ridha, “we can treat the root cause.”