Report details damage to sensory nerve cells with Pompe gene therapy in case
Woman's symptoms eased, but did not fully resolve, after treatment with AT845
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A middle-aged woman with late-onset Pompe disease (LOPD) developed damage to her sensory nerve cells after receiving the gene therapy candidate AT845 — in development as a Pompe disease treatment — in a clinical trial, according to a new case report.
While the woman’s symptoms, particularly reduced sensations in her hands and feet, gradually eased after steroid treatment, signs of damage had not fully resolved three years later, the researchers noted.
Given the outcome in this case, the team is now recommending close monitoring and immediate care for nerve-related symptoms for all people receiving gene therapies.
“Even though there is not a specific treatment, a pulse of steroids could be considered as a therapeutic approach if patients develop this complication,” the scientists wrote.
The case report, “Sensory neuronopathy secondary to Gene Therapy with AT845 for Pompe Disease,” was published in the journal Neuromuscular Disorders.
A genetic condition, Pompe is caused by mutations in the GAA gene, which provides instructions for making acid alpha-glucosidase, an enzyme that helps break down glycogen, a stored form of sugar. When this enzyme is missing or not working properly, glycogen builds up to toxic levels in cells, especially muscle cells, leading to Pompe symptoms. LOPD is a form of the disease that manifests at any time after the first year of life, from childhood to late adulthood.
Enzyme replacement therapy, which provides the enzyme missing in Pompe, is the standard treatment for most patients. However, it requires lifelong infusions, and clinical response may decrease over time.
Gene therapies are being developed in Pompe as a way to deliver a working version of GAA to patients. These therapies use an adeno-associated virus (AAV) as a vehicle to deliver their genetic cargo.
AT845 developed to improve motor function in Pompe
AT845 is an experimental gene therapy intended to help improve motor function and prevent respiratory failure in people with Pompe.
In development by Astellas Gene Therapies, it is being tested in the Phase 1/2 FORTIS trial (NCT04174105), which is slated to run through 2035. The trial is evaluating AT845’s safety and effectiveness in adults with LOPD.
While elevated levels of liver enzymes are the most common side effect of AAV-based gene therapies, less is known about side effects involving the nervous system.
Now, researchers in the U.K. and Spain have described the clinical features of a 49-year-old woman with LOPD who developed sensory neuronopathy after receiving AT845 in FORTIS. That trial was placed on a clinical hold by the U.S. Food and Drug Administration in 2022 due to a case of peripheral sensory neuropathy; the hold was lifted a year later.
Sensory neuronopathy is a type of nerve damage that affects the cells responsible for feeling sensations such as touch, pain, and temperature.
This patient had been diagnosed at age 38 with LOPD, after two years of progressive leg weakness. She had been treated with the ERT Myozyme (alglucosidase alfa, sold in the U.S. as Lumizyme) since her diagnosis and had tolerated it well.
At the screening assessment for the FORTIS trial, she had leg weakness, needed a walking stick outdoors, and used noninvasive ventilation to help her breathe at night. Her sensory exam was normal.
She received the steroid prednisone starting one day before her one-time AT845 infusion, experiencing a chest rash immediately that resolved with cetirizine, an antihistamine.
During the first weeks after treatment, the woman reported feeling less tired and no longer needing a stick to walk. After two months, steroids were gradually reduced per protocol. However, because her liver enzymes rose to twice the normal level, prednisone treatment was continued before the dose was reduced again and ultimately stopped.
Sensory nerve responses absent or reduced for woman in all 4 limbs
About 2.5 months after the AT845 infusion, and after prednisone had been stopped, the woman developed tingling and burning sensations in her hands and feet, especially at night. She also had reduced sensation in her palms, fingers, soles, and toes, more severely on the right hand and left foot. Her walking became unsteady, and she again needed a walking stick, the researchers detailed.
Nerve conduction studies and electromyography tests that assess how well nerves and muscles respond to stimulation showed findings consistent with sensory neuronopathy. Sensory nerve responses were absent or reduced in all four limbs, while motor nerve responses remained normal.
Blood, brain, and genetic tests were normal, with the exception of high protein levels in the cerebrospinal fluid, the fluid surrounding the brain and spinal cord.
“We hypothesized that the neuronopathy could be secondary to a potential inflammatory cause since symptom onset coincided with the reduction of steroids and there was an increase in proteins in the CSF,” the team wrote.
[Sensory neuronopathy] should be considered a potential adverse effect of gene therapy using AAV.
The woman was treated with steroids and pregabalin for nerve pain. Her symptoms then stabilized, and steroids were progressively tapered off. However, abnormal sensations at night remained difficult to control, according to the researchers.
At 18 months after symptom onset, mild sensory symptoms persisted in her fingers and toes, although her walking had improved. Three years after infusion, the woman still had reduced sensation in her fingers and toes, but did not show signs of ataxia, or loss of coordination, per the report.
Ultimately, the biological processes that led to this woman’s complications could not be fully identified, according to the researchers. The team noted, however, that based on this case report, sensory neuronopathy “should be considered a potential adverse effect of gene therapy using AAV.”
