Skip to Main Content

Researchers investigating a potential new therapy for an ultra-rare genetic disease have made an important discovery — one that could have broader implications and may lead to a lasting treatment for a severe, debilitating form of Crohn’s disease and, perhaps, a host of other grievous medical conditions.

The gene therapy technique was initially developed to potentially treat rare genetic diseases in children, such as X-linked chronic granulomatous disease, or X-CGD. Infants with X-CGD suffer from a variety of symptoms including severe bacterial and fungal infections as well as persistent gastrointestinal symptoms like vomiting and diarrhea which can interfere with normal growth.

Dr. Bobby Gaspar, a physician-scientist and co-founder and chief executive officer of Orchard Therapeutics has worked for 25 years in the field of gene therapy using hematopoietic stem cells (HSCs), which reside in the bone marrow and give rise to mature blood cells of all types, including the white blood cells that comprise the immune system. In children with diseases caused by malfunctioning or missing genes, Gaspar and his colleagues have developed a gene therapy approach to remove HSCs from an affected patient, insert a corrected gene into the HSC genome using a carrier called a lentiviral vector, and infuse the cells back into the patient’s body. When the gene-corrected HSCs stably engraft in the bone marrow and begin producing new blood cells, it creates the potential for lasting disease correction.

“You have to put the patient front and center of everything,’’ Gaspar says. “We didn’t initially set out to create a company. We set out to address some of the world’s most devastating diseases, and we have seen great promise every step of the way.”

Dr. Bobby Gaspar, co-founder and chief executive officer of Orchard Therapeutics

Despite decades of data behind the process, the full clinical potential of HSC gene therapy is just coming into focus.

A potential breakthrough scientific discovery

In studying patients with X-CGD, researchers made a discovery that could potentially change the way treatment for other diseases is approached. They observed that when X-CGD patients were treated with investigational HSC gene therapy, it seemed to improve the underlying immune system problems and appeared to reduce associated symptoms of colitis in certain cases — which warranted further investigation.

Colitis is inflammation of the digestive track that causes frequent or sudden abdominal discomfort and pain and can sometimes be so severe that, despite intensive therapy, sufferers end up having bowel resections. There are several types of colitis but the most common occur in people with inflammatory bowel diseases, such as ulcerative colitis and Crohn’s disease. Interestingly, a subset of Crohn’s disease patients who have mutations in both copies of a gene called NOD2 typically present with a more severe and untreatable form of the disease.

If it’s possible that the genetic correction could improve colitis symptoms in ultra-rare X-CGD, Gaspar hypothesized, “could we use the same approach for more prevalent diseases, such as a genetic subset of Crohn’s?’’

Much of this research is in the very early stages, but scientists at Orchard Therapeutics have studied HSC gene therapy in more than 160 clinical study patients with seven different diseases using this approach. “The first patients were treated over 10 years ago with a single administration of HSC gene therapy,’’ Gaspar says, “and we’ve seen a durable effect over this time.’’

Now, Gaspar and the team at Orchard Therapeutics are delving deeper into the potential for correcting NOD2 mutations and rigorously evaluating the pre-clinical data, while also investigating potential uses for HSC gene therapy in other more prevalent diseases.

Working to address difficult to-treat neurodegenerative diseases

Orchard Therapeutics is also studying HSC gene therapy to treat neurodegenerative diseases. Its most advanced program is in metachromatic leukodystrophy (MLD), a devastating rare neurodegenerative disease that robs a child of their ability to talk, walk and engage with their families and the world around them.

“In clinical trials we have seen a potentially durable correction of disease in patients with MLD,’’ Gaspar says. “Through the genetic modification of HSCs, we have a route to cross the blood-brain-barrier and deliver genes into the central nervous system. We have taken that approach and applied it to rare conditions. So, why can’t we use it to treat more common forms of neurodegeneration?’’

To find out, Orchard Therapeutics has begun investigating the potential of HSC gene therapy to treat amyotrophic lateral sclerosis, or ALS, a common neurodegenerative condition, as well as a genetic subset of frontotemporal dementia, or FTD.

But it takes time. “Our vision is to deliver on our later-stage programs in rare diseases while building expertise in manufacturing and regulatory approvals, and at the same time develop these gene therapies for larger populations of patients,’’ Gaspar says.

Through this research and discovery, Gaspar says he has not lost sight of what drives him. “You have to put the patient front and center of everything,’’ he says. “We didn’t initially set out to create a company. We set out to address some of the world’s most devastating diseases, and we have seen great promise every step of the way.’’

For more information, visit