Enzyme replacement therapy found effective in Sanfilippo type A mice
Denali to seek FDA approval to start clinical trials of DNL126 in humans
The investigational, brain-penetrating enzyme replacement therapy DNL126 was found to correct neurological signs of Sanfilippo syndrome type A in a mouse model, according to its developer, Denali Therapeutics.
Now, the biopharmaceutical company plans to seek U.S. Food and Drug Administration permission — via an investigational new drug application or IND — to start clinical trials in humans.
“Denali plans to submit an IND application for DNL126 in the first half of 2023,” the company said in a press release.
Results from the mouse study were reported in a recent oral presentation by Annie Arguello, PhD, Denali’s director of translational sciences. Arguello spoke at the 19th Annual WORLDSymposium in Orlando, Florida.
“There are no approved therapies for [Sanfilippo syndrome type A], representing a high unmet medical need,” the researchers wrote in the poster that accompanied the presentation.
Developing potential treatments for Sanfilippo
Sanfilippo syndrome, also called mucopolysaccharidosis type III (MPS III), is a genetic condition marked by inherited deficiencies in enzymes that break down the complex sugar molecule heparan sulfate. As a result, this sugar builds up to toxic levels inside cells, causing damage and inflammation, especially in brain tissue.
There are four types of Sanfilippo syndrome: those with type A are deficient in the SGSH enzyme. This is the most common type, and a more severe form, with symptoms typically appearing earlier and progressing faster.
Enzyme replacement therapy, known as ERT, is a potential Sanfilippo type A treatment in which a lab-made version of the missing SGSH enzyme is provided by an external source.
However, ERT development has been hindered by its inability to cross the blood-brain barrier — a protective membrane that prevents large molecules and microbes in the bloodstream from entering the brain.
Denali’s enzyme transport vehicle (ETV) technology exploits the transferrin receptor (TfR), a protein that transports iron from the bloodstream, across the blood-brain barrier, and into the brain.
DNL126 is composed of SGSH enzymes attached to an antibody fragment carrying an engineered TfR binding site.
Administered directly into the bloodstream (intravenously), the therapy is designed to bind to TfR and cross the blood-brain barrier into the brain. Once there, DNL126 may help break down heparan sulfate and address Sanfilippo’s cognitive, behavioral, and physical symptoms.
A similar ETV-based ERT by Denali is now undergoing Phase 1/2 clinical testing in children with MPS II, also called Hunter syndrome. This disorder is marked by a deficiency of the IDS enzyme that also breaks down complex sugars, causing tissue damage.
In the DNL126 preclinical study, healthy mice were engineered to produce a portion of the human TfR. Intravenous administration showed a dose-dependent increase of DNL126 in the brain, compared with mice without human TfR.
To demonstrate DNL126’s utility in Sanfilippo A, mice carrying human TfR, modified to produce very low levels of the SGSH enzyme, were given 12 weekly injections into the abdomen at low and high doses.
After treatment, excess heparan sulfate levels in brain tissue dropped significantly in a dose-dependent manner, as did levels in the cerebrospinal fluid, the liquid that circulates around the brain and spinal cord. The liver also showed a significant reduction in heparan sulfate with DNL126.
Looking more closely, the high dose of DNL126 significantly decreased heparan sulfate in different types of brain cells, including neurons that transmit electrical signals, astrocytes that support neurons, and microglia, the immune cells of the brain.
Because the SGSH enzyme is found in lysosomes, the cellular compartments responsible for breaking down and recycling molecules, heparan sulfate buildup disrupts lysosomal function. DNL126 treatment corrected abnormal levels of proteins and fat-like lipids associated with impaired lysosomes, consistent with improved lysosome function.
Finally, using three different biomarkers, DNL126 treatment also corrected disease-related brain inflammation.
Denali is collaborating with Sanguine Biosciences on a U.S.-based Sanfilippo type A natural history study (NCT05523206) to monitor behaviors, find blood-based biomarkers, and shed more light on the disorder. The study is expected to enroll 20 participants, ages 4 months to 13 years, with at least 10 patients younger than age 4.
According to Sanguine’s website, the natural history study will require seven visits over the course of about two years. Visits will include behavioral assessments and the collection of blood samples. Participants will be compensated up to a total of $1,400.