Systemic AAV Gene Therapy Extends Lifespan in Alpha-Mannosidosis Cat Model, Even at Late Stages
Late Diagnosis and Therapeutic Barriers
Alpha‑mannosidosis is a lysosomal storage disorder caused by deficiency of the enzyme alpha‑mannosidase, leading to widespread storage lesions throughout the brain and peripheral tissues. While early diagnosis and treatment are highly effective in animal models, most clinical diagnoses occur after symptom onset. We therefore sought to determine whether gene therapy could be effective even in end‑stage disease.
Systemic AAV Delivery, a Novel Approach
We administered the AAV‑based vector AAVhu.32‑fMANB systemically via the carotid artery, delivering it directly into the circulation. In cats with mild early symptoms, brain lesions were nearly eliminated, whereas cats with advanced disease showed modest improvements in several clinical parameters. Increasing the vector dose did not yield additional clinical benefit.
Partial Rescue, Limitations, and Outlook
Advanced‑stage cats exhibited extended survival and slight improvements in behavior and weight maintenance after treatment. However, complete symptom reversal was not achieved, and dose escalation proved ineffective. Nonetheless, the partial correction demonstrated that gene therapy can slow disease progression.
Future Implications
These findings reinforce the critical importance of early screening and intervention for lysosomal storage diseases such as alpha‑mannosidosis. Translation to human patients will require strengthened early‑diagnosis programs and more efficient vector designs.
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 demonstrates that gene therapy can provide a measurable benefit even for patients with alpha‑mannosidosis diagnosed at a late stage. These results may help patients and their families slow disease progression and preserve quality of life.