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Pre-Clinical Gene Therapy Study Shows Promise for Niemann-Pick Type A

Article In Brief

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.”


“I think its a step [forward] and does not mean gene therapy for people with this disease is around the corner—but it may be a future option.”—DR. ELIZABETH BERRY-KRAVIS

Study Design, Findings

NPD-A is a rare disease in which mutations in the hASM gene impair the activity of an enzyme critical for lysosomes' cellular function. As a result, metabolic products including sphingomyelin and cholesterol build up in the brain and other organs. Most affected infants are diagnosed between the ages of 3 to 6 months, when they develop hepatosplenomegaly and stop reaching milestones for growth and weight gain. Regression of neurologic function begins around year one, accompanied by interstitial lung disease. Death usually occurs in early childhood.

Gene therapy has long been considered a suitable treatment for NPD-A, in part because even a slight increase of the ASM enzyme, reaching as little as 5 percent to 10 percent of normal activity, appear to be sufficient to prevent neurological dysfunction. “Moreover,” the new paper noted, “hASM is a secreted enzyme that can be taken up by cells, thus enabling cross-correction of noninfected cells by neighboring transduced cells (bystander effects).”

However, previous treatment studies in mice and non-human primates resulted in improvements only at the injection site and immediate surrounding areas. At the same time, the high focal expression of hASM at those sites triggered inflammation, weight loss, and motor deficits. Those findings led the investigators to seek an administration route that would disseminate the ASM more broadly throughout the brain, avoiding the focal spots with high levels of expression.

Injection into the CM cistern resulted in low expression of the hASM gene in the brain, said the senior author of the paper, Maria Dolores Ledesma, PhD, a researcher at the Centro de Biologia Molecular Severo Ochoa in Madrid, Spain. But, Dr. Ledesma said, “This is exactly what we need in the case of NPD-A. We know that too much transduction leads to inflammation.”

The CM injection route led to cortical and subcortical expression of the gene, including deep brain areas not previously reached in earlier studies, such as the thalamus, hypothalamus, and basal ganglia. Expression was also seen in the hippocampus, an area not previously reached in other studies. Although the levels there were very low, they were sufficient to improve hippocampus-dependent memory in the mice.

“We expected to improve safety and to have good results in brain areas close to the site of injection,” Dr. Ledesma said, “but were very happy when we saw that the strategy impacted also very deep brain areas and that this impact had functional benefits such as memory improvement.”

In addition to the effects seen in the brain, the study found expression of ASM in the liver and in the cervical, thoracic, and lumbar regions of the spinal cord up to three months after injection. Whether due to the ability of the AAV9 vector to cross the blood-brain barrier, or the leakage of the ASM protein, the result was also resulted in a reduction of sphingomyelin in the liver, as well as less inflammation in that organ.

Still, effective treatment of non-CNS effects of NPD-A is expected to require a more broadly systemic treatment. The new paper noted, for example, that enzyme replacement therapy (ERT) by intravenous infusion of rhASM “seems to be successful in treating systemic, but not CNS, symptoms in ASM-knockout mice and in patients with NPD-B.

“We, therefore, believe that the combination of AAV-based gene therapy into CM followed by ERT offers an optimal approach for the comprehensive treatment of NPD-A. In our opinion, this study would guide clinical development not only for NPD-A, for which no treatment is currently available, but also for other monogenic brain LSD [lysosomal storage disorders] having a substantial impact on public health and reinforcing the therapeutic value of AAV-based genome editing.”

Expert Commentary

Marc C. Patterson, MD, FAAN, FRACP, professor of neurology, pediatrics and medical genetics at Mayo Clinic Children's Center in Rochester, MN, said the study was “thoughtfully designed and skillfully executed. It builds on the results of previous investigations and has very encouraging results. This has potential implications for treating a large number of lysosomal storage disorders in humans.”


“We are currently designing new pre-clinical experiments to evaluate the long-term safety of the gene therapy approach for NPD-A. 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.”—DR. LLUIS SAMARANCH


“The main take-home message is that they found a route and a virus to target a really rough area of the brain....getting the mouse data is probably going to be the easiest part. Translating these results to patients will be challenging and will likely take some time.”—DR. RANDY J. CHANDLER

Dr. Patterson, who has been involved in prior studies of NPD, said he remains cautious in anticipating what the new approach may mean for human clinical trials.

“It must be remembered that a mouse brain is much smaller than a human brain, so it may not be realistic to expect such widespread expression of the gene,” he said. “Achieving similar results would require very early diagnosis and treatment in humans, in whom the deficits are usually more severe, and the extent of irreversible injury is usually greater at the time of diagnosis.”

Moreover, he added, “I think it is too early to say that this is a ‘cure’ even in these mice. They will require much longer-term studies. These mice had deficits, but they were relatively early in the course of the disease.”

Elizabeth Berry-Kravis, MD, PhD, professor of neurology at Rush University in Chicago, has studied Niemann-Pick disease type C, a more slowly progressing disorder featuring similarities in the lysosomal lipids being accumulated. Similar gene therapies for NPD-C, she said, are in development. But she agreed with Dr. Patterson that effective treatment results will be harder to achieve in humans than in mice, simply because of brain size differences.

“I think it's a step [forward] and does not mean gene therapy for people with this disease is around the corner—but it may be a future option,” Dr. Berry-Kravis said.

Randy J. Chandler, PhD, staff scientist at the National Human Genome Research Institute, was the first author of a 2017 paper on a systemic gene-therapy treatment for NPD-C using the same viral vector as in the current paper. Although type C progresses less quickly than does type A, he said, it is still devastating for families.

“It's still really sad,” he said. “The parents are desperate. Every day they see their kid getting a little sicker and there's not much they can do about it.”

He applauded the success that Dr. Ledesma's group had in finding a way to deliver a therapeutic dose of the gene into the brain. “That's probably why this paper is published in such a high-impact journal,” Dr. Chandler said. “And they went the next step, documenting the effect in non-human primates.”

The main take-home message, he said, is that “they found a route and a virus to target a really rough area of the brain.” Even so, he said, “getting the mouse data is probably going to be the easiest part. Translating these results to patients will be challenging and will likely take some time.”

He pointed to disappointing results in a clinical trial of a systemic treatment for NPD-C, the sugar molecule 2-hydroxypropyl-β-cyclodextrin, which had looked promising in mouse studies as well as in a pilot clinical trial. In November, however, Mallinckrodt Pharmaceuticals announced in a conference call with investors that the drug showed no statistical benefit in a year-long randomized trial involving 56 children and youths. Although investigators had expected both the active-treatment and placebo groups to show signs of disease progression—albeit less so in the treatment group—neither arm progressed at all, a puzzling finding.

Although that trial involved NPD-C, “I am sure it was a disappointment for the whole NP community,” Dr. Chandler said. “So the positive findings from this NPD-A paper should be especially welcomed.”


Drs. Samaranch, Bankiewicz, Chandler, Ledesma had no disclosures. Dr. Berry-Kravitz has been reimbursed for travel by Asuraen Pharmaceuticals, Mallinckrodt Pharmaceuticals, Acadia Pharmaceuticals, Neuren Pharmaceuticals, Ionis Pharmaceuticals, Roche Pharmaceuticals, Cydan Pharmaceuticals, AMO Pharma, Ovid, Sucampo Pharmaceuticals, and Vtesse; all consulting fees were paid to her institution. Dr. Patterson has received honoraria or travel expenses for consulting, or for service on scientific advisory board from Amicus Therapeutics, IntraBio Pharmaceuticals, Novartis Pharmaceuticals, Orphazyme Pharmaceuticals, Shire Pharmaceuticals, and Vtesse; he holds stock in IntraBio, receives a stipend for editorial duties as editor in chief for Journal of Child Neurology and Child Neurology Open from Sage, royalties for his editorial role at Up-To-Date, and a stipend and travel expenses for editorial duties from the Society for the Study of Inborn Errors of Metabolism.

Link Up for More Information

• Samaranch L, Pérez-Cañamás A, Soto-Huelin B, et al. Adeno-associated viral vector serotype 9-based gene therapy for Niemann-Pick disease type A Sci Transl Med 2019;11(506). pii: eaat3738.
    • Salegio EA, Samaranch L, Jenkins RW, et al. Safety study of adeno-associated virus serotype 2-mediated human acid sphingomyelinase expression in the nonhuman primate brain Hum Gene Ther 2012; 23:891–902.
      • Chandler RJ, Williams IM, Gibson AL, et al. Systemic AAV9 gene therapy improves the lifespan of mice with Niemann-Pick disease, type C1 Hum Mol Genet 2017;26(1):52–64.