Morquio syndrome, also known as mucopolysaccharidosis type IV (MPS-IV), is a rare genetic disorder that is part of a group of eleven lysosomal storage diseases known as mucopolysaccharidoses (MPS diseases). It is caused by deficiency of the enzyme N-acetylgalactosamine-6-sulfatase (GALNS), which is responsible for the breakdown of glycosaminoglycans (GAGs) known as keratan sulfate and chondroitin-6-sulfate. Due to enzyme deficiency, these GAGs accumulate in cells, blood and tissues throughout the body, eventually causing damage. There are two types of Morquio syndrome - type A and type B. Both are caused by mutations in the GALNS gene, but they differ in their clinical features and severity.
Signs and Symptoms of Morquio Syndrome (MPS-IV) Drug Industry
Some key signs and symptoms seen in patients with Morquio Syndrome (MPS-IV) Drug include skeletal dysplasia, short stature, spinal deformity, joint abnormalities, hearing loss, corneal clouding, heart issues and lung dysfunction. Skeletal problems are usually the most visually obvious and disabling features. Due to abnormal bone growth and development, patients often have shortened upper arms and legs, flat facial features, cervical spinal instability and swayback. Severe spinal cord compression leading to paralysis is not uncommon. Valvular heart disease is also a major clinical manifestation seen in the majority of Morquio syndrome patients.
Current Treatment Options and their Limitations
Currently, treatment of Morquio syndrome involves managing symptoms through surgical interventions and supportive care. Orthopedic surgeries like spine correction and joint replacement are commonly performed to improve mobility and quality of life. Other interventions may include hearing aids, ventilation support if required, and medications to manage heart complications. While these approaches help address some clinical issues, they do not slow disease progression or correct the underlying metabolic abnormality caused by GALNS deficiency. Enzyme replacement therapy (ERT), the standard therapy for many MPS diseases, is not viable for Morquio syndrome since the recombinant enzyme cannot efficiently cross the blood-brain barrier. Hematopoietic stem cell transplantation (HSCT) has also shown limited benefit. Thus, there remains a high unmet need for effective disease-modifying treatments for this often-devastating disorder.
New Experimental Therapy in Clinical Trials
A promising new approach currently under investigation is the use of gene therapy to deliver functional copies of the GALNS gene directly into the body. In February 2022, BioMarin Pharmaceutical announced positive preliminary results from an ongoing Phase 1/2 study of its investigational gene therapy valoctocogene roxaparvovec, also called BMN 307, in patients with type A or B Morquio syndrome. This therapy involves using an AAV5 viral vector to carry the corrective GALNS gene and deliver it systemically intravenously. Six patients ages 5 to 35 years were dosed across two cohorts in the dose-escalating study. At the 6-month analysis, investigators reported clear signs of response in multiple disease domains.
Improvements in 6-Minute Walk Test Distance
Significant increases in 6-minute walk test (6MWT) distance were seen in all patients 6 months after receiving BMN 307 gene therapy. The 6MWT is used to evaluate functional exercise capacity and endurance levels in patients with cardiopulmonary or musculoskeletal disorders. An increase in walking distance indicates improved mobility and lessened fatigue. For the high dose cohort, mean 6MWT distance increased by 49 meters, a positive response.
Reductions in GAG Biomarkers
Levels of urinary keratan sulfate (KS) and chondroitin-6-sulfate (C6S), two GAG biomarkers used to monitor disease progression, decreased substantially in all patients post-treatment. Reductions ranged from 34-90% for KS and 33-86% for C6S. Since GAG accumulation is the underlying pathology in Morquio syndrome, lowering biomarker levels directly correlates to less storage and cellular/tissue damage.
Improvements in Pulmonary Function
Mean forced vital capacity (FVC), a measure of lung volume and respiratory health, increased by 9% in the high dose group. This holds promise for stabilizing or reversing the progressive respiratory issues seen in Morquio syndrome patients over time.
Tolerability and Safety Profile
To date, treatment with BMN 307 appears to have a manageable safety profile, with no unexpected drug-related serious adverse events reported. The most common side effects have been mild infusion-related reactions. No patient discontinued treatment due to safety issues. Overall, these initial clinical trial results suggest valoctocogene roxaparvovec could potentially be the first disease-modifying treatment option for Morquio syndrome. However, longer term follow up is still needed to confirm durability of response and fully establish the gene therapy's safety and efficacy profile.
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