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The gene therapy revolution is well underway. This relative newcomer to the world of medicine is getting much well-deserved attention, and scientists are optimistic at the promise of this powerful platform to deliver a new set of tools to treat tough-to-tackle disease.  

While often referred to as a single technology, there are different approaches to gene therapy, including the type of cell modified, the vector and the delivery mechanism.  

So how do they differ? 

1. Type of Cell

The type of cell that is genetically modified plays 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. Hematopoietic (blood) stem cells, or HSCs, are particularly appealing because of their intrinsic ability to self-renew, which means that these cells serve as a 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. Thus, correcting HSCs offers the potential to correct many different diseases and by crossing the blood-brain barrier, potentially correct certain neurodegenerative conditions. 

2. Vector

 While there are multiple methods of introducing genetic materials into cells that are being studied, the most well-studied and commonly used are viral vectors. Different types of viral vectors can be used to deliver a gene into the cell. Importantly, some vectors do not integrate into the genome of the cell, while others, such as the lentivirus vectors 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. 

3. Delivery 

Gene therapy researchers must also consider the best way to deliver a gene to a particular cell type. In some cases, a vehicle (usually a viral vector) 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 that carries the gene is given directly into the body. In some cases, the cell intended for correction 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 called an ex vivo gene therapy.  

How does ex vivo HSC gene therapy work?   

Scientists begin by collecting and isolating a patient’s own HSCs, either from the bone marrow or from the bloodstream. Then they introduce a working copy of the missing or faulty gene into these cells using a viral vector. Finally, they return the gene-corrected cells back to the patient, where they can embed themselves in the bone marrow (engraftment). When the viral 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. 

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. Based on the success of this approach in rare disease, it will now be investigated for less-rare conditions with high unmet medical need, such as ALS and certain genetic subsets of frontotemporal dementia (FTD) and Crohn’s disease.  

To learn more about the promising potential of HSC gene therapy,