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The field of gene therapy has moved from promising scientific research to medical reality. With the potential to permanently correct genetic disorders with a one-time treatment, many gene therapies are getting well-deserved attention, and scientists are optimistic about the possibility of this therapeutic modality to address a range of severe diseases.

Gene therapy is designed to provide functional copies of a faulty gene that is not working properly. Genes are the genetic blueprints for proteins and sometimes a mutation (essentially a change in that blueprint) can result in a non-functioning or missing protein, which causes a particular disease. Gene therapy can potentially restore the production of a needed protein within a patient’s cells.

“While often referred to as a single technology, there are different approaches to gene therapy,” said Fulvio Mavilio, Ph.D., a luminary in the field and the chief scientific officer of Orchard Therapeutics. “Even within the same general types of gene therapy, there are distinct differences, including the type of cell modified, the route of administration, and the viral vectors, which are genetically modified viruses engineered to serve as delivery vehicles.”

What is a viral vector?

While gene therapy scientists are developing many ways to deliver a needed gene to cells in the body, nature has provided one of the most efficient tools — viruses. The viruses we encounter in everyday life have evolved to efficiently enter our body and pass genetic material into our cells during an infection.

“Over the last 25 years, researchers have identified ways to inactivate specific viruses so that they are incapable of causing disease and then engineer them to deliver new genetic material into human cells,” said Dr. Mavilio. “Removing the disease-causing parts of a virus leaves enough space, or capacity, to make the engineered virus into an effective gene delivery vehicle.”

How are viral vectors used in Orchard’s gene therapy approach?

Orchard’s approach to gene therapy is designed to deliver a functional version of the mutated gene, or transgene, to a patient’s own blood stem cells — called hematopoietic stem cells, or HSCs — to produce the desired therapeutic protein. The process begins by collecting and isolating a person’s own HSCs. Then, in a specialized manufacturing facility, the patient’s HSCs are combined with the viral vector carrying the functional transgene that encodes the needed protein. The vector enters the cell in a process called transduction and introduces the functional transgene to produce the therapeutic protein.

What are lentiviral vectors, and why are they well-suited for HSC gene therapy?

Not all viruses — and viral vectors — are alike. Different types of viral vectors are used in gene delivery. The viral vector used is largely dependent on the disease and cell type that needs correcting. Lentiviral vectors, the type of vector that Orchard uses, are particularly well-suited for HSC gene therapy, as they derive from viruses that have the unique ability to integrate into the genome of the target cells.

This is an important characteristic because when HSCs divide, the integrated transgene is passed on to future generations of that cell, offering a potentially stable and lasting supply of gene-corrected cells. HSCs generate a large variety of differentiated cells in the body, including specialized cells lining the gut or those capable of infiltrating the brain, which allows delivery of therapeutic proteins  to many  otherwise difficult-to-treat organs and tissues. 

Are all lentiviral vectors used in gene therapy the same?

Most of the lentiviral vectors used by Orchard and other companies in the field have a common backbone, but there may be substantial differences in the vector design and particularly on the choice of the genetic elements, such as promoters and enhancers, used to drive the expression of the therapeutic transgene.

According to Dr. Mavilio, “Orchard uses lentiviral vectors that contain promoters derived from the human genome, and these promoters lack the strong enhancer activity typical of promoters derived from viruses. Human promoters are less likely to transactivate, or turn on, neighboring genes which may lead to off-target effects.” In its vector design, the company also customizes the way the transgene is regulated so that therapeutic protein production is matched with the needs of the cell or the surrounding tissue.

“Our vectors are designed to optimize transgene expression in the specific tissue or organ we are targeting and to minimize the risks of activating potential oncogenes that has been observed with the use of viral promoters.”

Fulvio Mavilio, Ph.D., chief scientific officer of Orchard Therapeutics

Are lentiviral vectors and AAV vectors similar?

A frequently used type of viral vector is based on the adeno-associated virus, or AAV. Generally, gene therapies based on AAVs are delivered directly into the patient’s body to transduce cells located in a variety of organsAAVs deliver the transgene to the nucleus of the target cell, but unlike lentiviral vectors, the transgene is not integrated into the cell’s genome, so it is not passed on when those cells divide. Therefore, AAV is typically used to transduce non-dividing cells, such as cells in the liver, eye, heart, and skeletal muscles.

Learn more about Orchard’s HSC gene therapy approach here.