Gene Therapy Stimulates Missing Enzymes in Rare Disease

(Genome Research Limited, Flickr)

11 Oct. 2022. Results from a clinical trial show an experimental gene therapy for Krabbe disease is safe and produces enzymes missing in children with the rare disease. Executives from Forge Biologics Inc. in Columbus, Ohio are presenting findings from the trial this week at meetings of the European Society of Gene and Cell Therapy in Edinburgh, Scotland and Alliance for Regenerative Medicine in Carlsbad, California.

Krabbe disease is a rare genetic neurological disorder affecting primarily infants, caused by mutations in the galactosylceramidase or GALC gene. The GALC gene provides instructions for enzymes to break down certain fats in the body, including those that regulate production of myelin, the protective coating on neurons or nerve cells in the brain and elsewhere in the body. Without the GALC enzymes, fats can turn toxic and prevent myelin from forming, causing damage around neurons. Infants under the age of one year with Krabbe disease often show irritability, weakness, and feeding difficulties, and later have difficulty moving, chewing, swallowing, and breathing, as well as vision loss and seizures.

Forge Biologics is both a developer of gene therapies for inherited diseases, and a provider of labs and manufacturing facilities to other gene therapy developers. The two year-old company specializes in gene therapies delivered by adeno-associated viruses, benign and naturally occurring microbes that infect cells, but don’t integrate with a cell’s genome and cause, at most, mild reactions. These viruses have become a favored method for delivering healthy or modified genes as treatments for genetic disorders.

Bone marrow transplant plus gene therapy

Forge Biologics’ lead product, code-named FBX-101, is a gene therapy for Krabbe disease. FBX-101 is derived from research by pediatric neurologist Maria Escolar at University of Pittsburgh, and chief medical officer at Forge Bio. The treatment combines gene therapy with an umbilical cord bone marrow transplant to relieve damage to central and peripheral neurons from Krabbe disease. Infants with Krabbe disease are given blood-forming stem cell transplants in bone marrow as the first part of FBX-101, and then a functioning copy of the GALC gene, delivered with adeno-associated viruses.

The early- and mid-stage clinical trial is enrolling six infants age 12 months or younger diagnosed with Krabbe disease at University of Michigan medical center. The first three patients receive a low dose infusion of FBX-101, while the other three children receive a higher dose. The study has no control or placebo group. The research team is looking mainly at the safety of FBX-101, tracking adverse responses to the treatments, as well as reactions to the hematopoietic stem cell transplants or HSCTs. Science & Enterprise reported in Jan. 2021 on FDA clearance for Forge Bio to begin the trial.

Forge Biologics says results from the trial so far show the children are tolerating the infusions well, with no humoral or antibody immune response to adeno-associated viruses that would pose a danger to the patients. In addition, the researchers found increases in GALC enzyme concentrations in the children’s blood plasma and cerebrospinal fluid or CSF, as well as improved brain development and motor activity, consistent with a healthier GALC gene.

“An update on our first cohort data,” says Escolar in a Forge Biologics statement, “demonstrates that intravenous FBX-101 after HSCT infusion was safe and well tolerated, including increased GALC enzyme activity in plasma and CSF, normal myelination of white matter, and normalization of motor development.”

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