AAV Gene Therapy Extends Survival in a Feline Alpha-Mannosidosis Model Even After Symptoms Progress
Late diagnosis, a barrier to treatment
Alpha-mannosidosis is a disease in which variants in the MAN2B1 gene leave the lysosomal enzyme alpha-mannosidase absent or dysfunctional, causing storage lesions in the brain and other tissues. Animal models have shown benefits from early diagnosis and treatment, but in clinical practice diagnosis often comes only after symptoms appear. In this feline study, starting adeno-associated virus (AAV) gene therapy after symptoms had progressed extended survival, but increasing the dose provided no additional benefit.
The researchers treated cats at 12 weeks of age. Although the paper’s title and discussion address advanced disease, the Results section classified this treatment time point as an intermediate stage. It therefore cannot be described definitively as an experiment in which treatment began at the terminal stage.
Carotid AAV delivery and dose comparison
The researchers administered the AAV vector AAVhu.32-fMANB, carrying the feline alpha-mannosidase gene, via the carotid artery. Doses were 5.0×10¹³, 7.5×10¹³, and 1.0×10¹⁴ vector genomes (vg) per kg of body weight, with three cats in each dose group.
Untreated cats had a mean survival of 17 weeks. Cats given the baseline dose of 5.0×10¹³ vg/kg at 12 weeks of age survived to a mean age of 43 weeks, significantly longer than untreated cats (P<0.001). Survival here refers to the time until euthanasia upon reaching humane endpoint criteria due to worsening condition, rather than time to natural death. Weight loss, reduced responsiveness to people, and behavioral changes were among the endpoint criteria; these were not reported as outcomes improved by treatment.
Increasing the dose did not further extend survival. All three dose groups lived longer than untreated cats, but the survival extension in the highest-dose group did not reach statistical significance. Thus, within the range tested, dose escalation cannot be said to have provided additional clinical benefit.
Partial recovery, limitations, and prospects
Brain tissue showed a partial reduction in storage lesions, with no clear differences among dose groups. Neurological abnormalities, including tremors and truncal ataxia, also persisted. Magnetic resonance spectroscopy and diffusion tensor imaging likewise did not provide evidence that the brain had recovered to a normal state.
In an earlier study cited by the paper, administering the same baseline dose at 6 weeks of age, during the early symptomatic stage, almost completely corrected brain lesions and resulted in a mean survival of 61 weeks. This is a comparison with a previous study, not a concurrent control group in the present experiment. The current findings suggest that partial treatment effects may be possible even after symptoms have progressed, while showing that dose escalation alone did not match the effects of early treatment.
The small number of animals in each dose group and the fact that this was not a study in humans are limitations. The results do not establish that patients’ survival or quality of life would improve. The study is available in the provided original paper.
The benefit of early diagnosis and treatment has been demonstrated in animal models of several lysosomal storage diseases. In a clinical setting, however, diagnoses are often not made until after patients become symptomatic. The lysosomal storage disease alpha-mannosidosis is caused by a genetic deficiency of lysosomal alpha-mannosidase, leading to the widespread presence of storage lesions throughout the brain and other tissues. In a feline model of alpha-mannosidosis, we previously demonstrated complete correction of the brain following delivery of AAVhu.32-fMANB via the carotid artery in the early symptomatic stage. Here, we investigate the efficacy of AAV gene therapy on globally distributed storage lesions in animals with advanced disease. Some improvements in clinical parameters were observed, however these improvements were less than in animals with less advanced disease. Although the treated animals were improved compared to untreated animals, increasing the vector dose did not further improve clinical outcomes. These results further demonstrate the importance of early detection and treatment of a lysosomal storage disease to successful outcomes. Despite this, partial correction extended the lifespan of diseased cats and may be medically beneficial to patients by slowing or stabilizing the progressive degenerative course of disease.
This study provides a basis for considering gene therapy development for alpha-mannosidosis even after symptoms have progressed. However, partial lesion correction and extended survival in cats do not establish a treatment effect in people. When designing follow-up preclinical studies, researchers could examine treatment timing, the amounts of vector and enzyme delivered to the brain, and neurological function together, rather than assessing dose increases alone. In particular, the persistence of neurological abnormalities despite longer survival provides a reason to evaluate survival and functional recovery separately. The potential for use in patients requires further study.