Gene therapy comes in many forms: Here’s my insight and overview of Orchard’s HSC gene therapy approach

By Bobby Gaspar, M.D., Ph.D.

September 8th, 2020

I feel very fortunate to have spent the past three decades and almost my entire professional career in the field of gene therapy, helping to shape its growth from what many people once thought of as science fiction into real, potentially life-changing medicines. The public interest and understanding of genetic medicines has likewise grown, with regular news coverage highlighting advancements that academics and the biopharma industry are making in this space.

What’s often underappreciated about gene therapy, however, is that it isn’t one single approach. Today, I want to provide some context on the types of gene therapy. I’ll walk you through the importance of the genetically modified cell types, the implications of viral vectors, discuss delivery mechanisms and finally share a bit more about the ex vivo hematopoietic stem cell gene therapy approach that Orchard employs.

First, it is important to understand that the cell types that we genetically modify play a role in the success, durability and safety of gene therapy. It is now possible to introduce genes into liver cells, brain cells, muscle cells, T cells or blood stem cells. Importantly, the hematopoietic (blood) stem cells or HSCs are central to Orchard’s approach. HSCs are particularly appealing because of their intrinsic ability to self-renew which means that these cells serve as the repository of stem cells for the lifetime of the individual. Gene-corrected HSCs can give rise to gene-corrected red blood cells, immune cells, and specialist cells like macrophages which disperse throughout multiple organ systems; and so, correcting HSCs offers the potential to correct many different diseases and by crossing the blood brain barrier, potentially correct certain neurodegenerative conditions.

Different types of viral vectors can be used to deliver a gene into the cell. Importantly, some vectors do not integrate the new gene into the genome of the cell, while others, such as the lentivirus vectors that Orchard uses, do integrate and can splice the new gene into the genome of the target cell. This means that if the corrected cell frequently divides, such as the case with HSCs, and the vector has integrated into the genome of the cell, then the new genetic information is passed on to the daughter cells. Ultimately, the new genetic material will be passed on with every cell division, thus creating a durable pool of genetically corrected cells.

Additionally, we have to think about the best way to deliver a gene to a particular cell type. In some cases, we will need to use a vehicle (usually a viral vector) that will carry the therapeutic gene into the body to target and hopefully correct a specific cell type, perhaps an eye cell. This is called in vivo gene therapy – where the vector which carries the gene is given directly into the body. In some cases, the cell you want to correct – which are often blood cells – can be taken out of the body, modified or corrected with the gene of choice and then given back to the patient. This is an ex vivo gene therapy and is the approach that Orchard takes.

Now that we have talked through some of the types of gene therapy, I’d like to close by talking specifically about Orchard’s gene therapy approach. We begin by collecting and isolating a patient’s own HSCs, either from the bone marrow or from the bloodstream. We then introduce a working copy of the missing or faulty gene into these cells using a lentiviral vector. Finally, we return the gene-corrected cells back to the patient, where they can embed themselves in the bone marrow (engraftment). When the lentiviral vector splices the new therapeutic (or working) gene into the HSCs’ genome, the cells can continuously pass the corrected gene on as they divide and differentiate.

Orchard is a leader in the field of HSC gene therapy. A deep body of evidence has shown that HSC gene therapy can deliver potentially curative effects for children with rare genetic diseases, particularly neurometabolic conditions (more about that in my next post!). We’re now building upon this foundation to expand the promise of HSC gene therapy into less-rare conditions with high unmet medical need, such as certain genetic subsets of frontotemporal dementia (FTD) and Crohn’s disease. Realizing the full potential of HSC gene therapies will depend on both continued research and innovation, as well as robust commercial preparation and execution. We at Orchard are committed to fostering those important activities in the months and years to come, as we work to realize the benefits of HSC gene therapy for patients around the world.

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