HSC gene therapy for neurological conditions: A route to deliver potentially corrective treatments for devastating genetic diseases

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

In my last post, I shared my perspective on the overall field of gene therapy and the distinctive characteristics of the hematopoietic stem cell (HSC) gene therapy approach that Orchard employs. Today, I’d like to continue that conversation and talk more about the power of HSCs to migrate across the blood-brain barrier and the potential of HSCs to treat conditions of the central nervous system (CNS).

It’s important to remember that the brain is the most important organ in the body, and we have evolved to develop mechanisms to protect it. One component of that protection is the blood-brain barrier—a cellular lining that creates a divide between the brain and general blood circulation. The blood-brain barrier is responsible for determining which proteins, molecules and cells can cross into the brain to maintain normal brain function. While this difficult-to-cross barrier protects the brain from dangerous toxins and other threats, it also presents a unique set of challenges for treating conditions of the CNS. It means that, for example, certain therapies can have difficulty penetrating the brain. However, there is an exceptional cell type which can overcome this challenge—the HSC. You might remember that I previously talked about how HSCs can differentiate into multiple cell types; importantly, some become specialist cells that can cross the blood-brain barrier and enter the brain.

Now that you know about this HSC attribute, I’ll walk you through how HSCs can potentially be used to achieve a therapeutic effect in the brain. When we return gene-corrected HSCs to the blood stream, a subpopulation of these HSCs can develop into cells that have a natural ability to cross the blood-brain barrier and distribute throughout the brain. Once in the brain, these cells further differentiate into specialist cells called microglial-like cells. Because these cells have been genetically modified, they can express the missing or faulty gene by secreting the gene product—which is a protein or enzyme—into the brain where it can be taken up by defective neurons, thus correcting the underlying enzyme deficiency causing the disease.

Now that you see the challenges associated with crossing the blood-brain barrier and the natural migration ability of HSCs, you can understand why HSC gene therapy may offer potential hope for patients with certain kinds of genetic neurodegenerative conditions.

Through our foundational work in metachromatic leukodystrophy and other neurometabolic and neurodegenerative conditions, we have been able to understand the mechanism by which HSC gene therapy can make a difference in the CNS and potentially prevent deterioration in the brain. Based on these observations, we believe the HSC gene therapy approach could be used to deliver therapeutic genes or proteins for other less-rare neurodegenerative conditions which have high unmet need.

I believe there is great potential for the application of HSC gene therapy in a growing range of neurometabolic and neurodegenerative disorders. I look forward to continuing to share our learnings and progress as we harness the power of HSCs and seek to bring potentially curative treatments to patients living with devastating conditions.

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