These therapies marked a significant turning point in healthcare, offering hope to those affected by these often-devastating conditions. While they demonstrated their efficacy in treating manifestations outside the brain, there are still discernible limitations to these standard-of-care therapies.
ERT has shown remarkable success in addressing conditions that primarily affect non-brain organs, such as Type 1 Gaucher's disease. This disease, caused by a single enzyme deficiency, leads to the accumulation of non-functional fat-laden cells in the liver, spleen, and bone marrow, resulting in impaired organ function and a reduced quality of life. Proactive ERT, which balances deficient endogenous enzymes with manufactured counterparts, not only alleviates the symptoms of Type 1 Gaucher's disease, but also reduces the risk of irreversible tissue and organ damage while restoring life expectancy.
Despite the significant progress achieved in manifestations outside the brain, ERT encounters its limitations when it comes to addressing neurological complications in diseases such as mucopolysaccharidoses (MPS). This set of diseases is characterised by deficiency in one of several enzymes that degrade glycosaminoglycans (GAGs). Patients with MPS, specifically types I, II, III, and VII, experience cognitive impairment, developmental issues, behavioural challenges, seizures, and progressive degenerative dysfunction, leading to childhood dementia. First-generation ERTs fall short in treating these neurological manifestations, as these enzymes cannot cross the blood-brain barrier (BBB). Although some supportive therapies exist, such as anticonvulsants for seizures, they provide only palliative relief and fail to address the progressive dysfunction. The only way to address these neurological manifestations would be to deliver the missing enzyme to the brain. To tackle these challenges, a new era of second-generation ERTs shows promise, fuelled by pioneering biopharmaceutical companies looking to revolutionise the rare disease landscape for patients with neurological manifestations.
The BBB, which evolved as a "protective shield" for the brain, selectively regulates the passage of substances into this vital organ. While small moieties, like oxygen, gain access to the CNS via diffusion, larger molecules with electrical charges are not transported. To overcome this protective process and deliver much-needed ERT to the brain, scientists work to harness the brain's own transport mechanisms, particularly transcytosis. This innovative approach involves engineering fusion proteins where the enzyme needed in the brain is fused with an antibody or antibody fragment. This moiety binds part of the transcytosis transport system, without adversely affecting its normal function. These ERT fusion proteins are piggy-backed into the brain, and any fraction of therapeutic enzyme to cross the BBB will access and distribute across the brain. The delivery of ERT to the brain has been optimised using insulin or transferrin receptors, ensuring their binding characteristics favour the potential uptake and release to transport ERT into the brain on the luminal aspect of the brain endothelium, within the cytoplasm, and at the abluminal aspect.
While transcytosis-based delivery of ERT is advancing, it still faces challenges in terms of pharmacokinetics, efficient brain transport, and regulatory approval processes. Achieving these milestones demands a collaborative effort among scientists, clinicians, patients, regulatory agencies, and pharmaceutical companies. Given the varied manifestations of these diseases among patients, assessing treatment responses using a single outcome measure, such as cognition, cannot be expected to assess the response in all patients.
In conclusion, the brave new world of ERT, with a focus on fusion proteins that exploit brain-specific transcytosis, holds the key to reshaping the lives of many individuals and families grappling with rare diseases involving neurological manifestations. We must continue to invest in research, foster interdisciplinary collaboration, and maintain commitment to improving the lives of those affected by these conditions. In doing so, we can unlock the door to a brighter future, in which rare diseases with debilitating neurological effects can be managed by exploring all the natural biology of health and disease, rather than allowing an unmet need of orphan diseases to remain.