GlycoNet to Build on ‘Encouraging’ Results of Stem Cell Gene Therapy

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Researchers from the Canadian Glycomics Network (GlycoNet) are developing a new combination therapy that’s showing promising preclinical results for Sanfilippo syndrome.

The therapy is designed to remove patients’ faulty cells, correct them, and return them back to the body, where they will replicate to produce new healthy cells.

“We are using a combination of gene therapy, stem cells and small molecules to restore metabolic defects in the patient’s brain cells,” Alexey Pshezhetsky, PhD, the study’s principal investigator, said in a press release. “First results in the mouse models of the disease are very encouraging.”

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Sanfilippo is a type of lysosomal storage disorder, which is characterized by the abnormal buildup of toxic substances in the body’s cells.

In Sanfilippo, children lack the functional enzymes needed to break down a type of sugar called heparan sulfate, which subsequently accumulates in the brain, severely damaging nerve cells. The dysfunctional enzyme results from mutations in any of four genes, each of which cause a different Sanfilippo type.

“Children display symptoms like dementia,” Pshezhetsky said. “They experience behavioral problems and sleep disturbance, lose the ability to speak and most of them die before the age of 20.”

Typically, lysosomal storage disorders that do not affect the brain are treated with enzyme replacement therapies that are injected into the bloodstream. These therapies are designed to restore levels of the lacking enzyme. However, in Sanfilippo, these therapies are ineffective as these enzymes can’t cross the blood-brain-barrier — a semipermeable membrane that shields the brain and spinal cord from the external environment — and reach the brain where they are needed.

“There is a physical barrier between the brain and the bloodstream that enzymes cannot pass through,” Pshezhetsky said. “So, in cases where enzyme replacement therapy is ineffective, we are looking for new treatments that can potentially cure or ameliorate the disease.”

Stem cells are a type of cell that has the ability to self-renew and are the body’s source of new cells during growth, or when damaged or dead cells need to be replaced. Hematopoietic stem cells are responsible for producing different types of blood cells.

The goal of the team’s therapeutic approach is to harvest these hematopoietic stem cells from Sanfilippo patients and use gene therapy to correct the disease-causing mutation. The corrected cells, now capable of producing a functional enzyme, will then be injected back into the patient. The stem cells will replicate to produce more healthy blood cells. These cells will be able to travel to the brain and replicate.

Since the stem cells will do the work of replicating once in the body, the therapy would only need to be administered once.

“It would be similar to a bone marrow replacement therapy,”  Pshezhetsky said. “Once you get the treatment, you have a life-long supply of cells you need.”

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Early results in mouse models of Sanfilippo are promising, according to GlycoNet, and the team is working on collecting more data in the hopes of eventually testing the therapy in patients. The approach may also be promising for other brain-affecting lysosomal storage disorders for which there are no effective treatments.

“About two-thirds of lysosomal storage disorders affect the brain. If we find out how to treat Sanfilippo syndrome, we can extend our knowledge to other similar diseases,” Pshezhetsky said.

“I think it’s important for people to know that recent discoveries lead to a paradigm shift for pediatric healthcare. Even if diseases are rare or ultra-rare we are not leaving patients behind but are developing customized ways to treat them.”