After receiving an adenoviral vector treatment of human ASM enzyme, transgenic mice with Niemann-Pick disease showed less accumulation of sphingomyelin, less damage to the brain and liver, and performed better in tests of motor function and memory.

Injecting the adenoviral vector treatment into the brain affected the cortex and hippocampus in mouse models of Niemann-Pick disease (left). White asterisks indicate cells that took up human ASM enzyme. Injections of the adenoviral vector treatment into the brains of mice with Niemann-Pick disease (right) reversed abnormalities in liver macrophages.

A new route for delivering gene therapy into the brain so that it is widely taken up without sparking an inflammatory reaction appears to be at least partially effective for the treatment of Niemann-Pick disease type A (NPD-A), according to preclinical studies described in a paper published August 21 in Science Translational Medicine.

Previous attempts had delivered working, humanized copies of the gene encoding for acid sphingomyelinase (hASM) into cold viruses, then injected them directly into areas of the brains of mice or non-human primates. As described in a 2012 paper by some of the same researchers involved in the current study, that approach—using adeno-associated viral vector serotype 2 (AAV2)—resulted in the gene getting into neurons only in the immediate area of the injection site. In turn, the highly focal expression caused an inflammatory reaction.

This time, the investigators infused adeno-associated viral vector serotype 9 (AAV9) carrying hASM into the cerebrospinal fluid (CSF) via the cerebellomedullary (CM) cistern. In non-human primates, this route for spreading the humanized gene resulted in more widespread expression in their brain and spinal cord cells without signs of toxicity. Likewise, in ASM-knockout mice, the functioning protein encoded by the gene was detected in the CSF and brain without triggering inflammation.

In addition, two months after administration, most of the neuronal consequences of the disease—motor and memory impairment, sphingomyelin accumulation, lysosomal enlargement, and neuronal death—had all been averted in the mice. And while it had only been injected into the CSF, beneficial effects were also seen outside the brain.

“Our results support CM injection for future AAV9-based clinical trials in NPD-A as well as other lysosomal storage brain disorders,” the paper concluded.

Scientists involved in the study and independent experts told Neurology Today that the findings represent just one more step in a long journey toward finding a cure for the rare but devastating neurodegenerative disease.

“The main new information in this paper is the mode of delivery of the gene-therapy vectors and showing the widespread distribution of the vector in a primate brain,” said study co-author Edward H. Schuchman, PhD, the Francis Crick Professor and vice chair for research in the department of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai.

“The efficacy studies in the ASM knockout mouse models are proof-of-principle for this approach. Compared to other gene therapy studies performed with this same mouse, the results are more extensive and in general better.”

The first author of the study, Lluis Samaranch, PhD, said that they will now be conducting additional safety studies at Ohio State University that they believe will pave the way for a clinical trial in humans.

“We are currently designing new pre-clinical experiments to evaluate the long-term safety of the gene therapy approach for NPD-A,” said Dr. Samaranch, assistant professor in the university’s department of neurological surgery. “When completed, these results will be presented to the FDA in support of an IND [Investigational New Drug] application and to discuss the initiation of a clinical trial.”

One of the paper’s senior corresponding authors, Krystof Bankiewicz, MD, PhD, professor of neurological surgery and a member of the Ohio State’s Neurological Institute, said: “With all these years of gene therapy development, and the experience of our four prior AAV-based clinical trials for other neurological disorders, we are very confident we can translate this exciting data into human clinical trials at the Ohio State University Wexner Medical Center within the next couple of years.”

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