Invasive techniques

- BBB transient disruption: This technique uses noxious agents, hyperosmotic solutions or ultrasound (mannitol, dimethyl sulphoxide, ethanol, metals, glycerol and polysorbate-80, X-irradiation, etc.) to shrink the brain’s endothelial cells by breaking down tight junctions, thus allowing various molecules to enter the cerebral tissue.

- Intracerebroventricular and intrathecal infusion: This technique uses injection or intraventricular infusion of therapeutic proteins directly into the cerebrospinal fluid (CSF). Animal studies on MPS IIIA show that continual infusion of replacement enzyme partially ameliorates clinical, histological, and biochemical aspects in MPS IIIA mice, when treatment begins at an early symptomatic stage [8]. Clinical trials with the same technique have been initiated in humans. Recombinant human heparan-N-sulfatase (rhHNS) administration via implanted intrathecal drug delivery device in twelve patients with MPS IIIA was found to be generally safe and well tolerated. The treatment resulted in a consistent decline of HS in the CSF, suggesting in vivo activity in the relevant anatomical compartment [9].

Non-invasive techniques

- Modification of the drug to enhance its lipid solubility: This technique involves chemical transformation of water-soluble molecules into lipid-soluble molecules that are capable of crossing the BBB [10].

- Use of transport/carrier systems: This technique involves chemical modification of small-molecule therapeutic drug to enable the use of endogenous transport/carrier systems that mimic the structure of related specific endogenous molecules. Glucose transporter type 1, large neutral aminoacid transporter type 1, cationic amino-acid transporter type 1, monocarboxylic acid transporter type 1, and equilibrative nucleoside transporter 1 are some of the most common endogenous carrier-mediated BBB transporters used as carrier systems for drug delivery [11].

- Inhibition of efflux transporters that impede drug delivery: This technique involves the pharmacological inhibition of select efflux transporters that prevent blood-to-brain drug uptake, examples of which include P-glycoprotein, breast cancer resistance protein (BCRP in humans and Bcrp in rodents), and multidrug resistance proteins (MRPs in humans and Mrps in rodents), etc. Among substrates transported by BCRP/Bcrp are chemotherapeutic agents (i.e., mitoxantrone), anthracyclines (i.e., etoposide and teniposide), and campothecin derivatives (i.e., topotecan and irinotecan). Transport of etoposide, cisplatin, and doxorubicin has been demonstrated though MRP6/Mrp6 [2,6].

- Trojan horse approach: This technique uses molecules such as endogenous ligands or monoclonal antibodies that, while acting as molecular ‘trojan horses’, bind exofacial epitopes on BBB receptor-mediated transport systems, thus triggering internalization of the receptor and the attached drug. This technique is being used to ferry drugs, proteins, and non-viral gene medicines across the BBB [2, 6].

- Chimeric peptides: This technique is being used for the transport of therapeutic compounds that can only be transported at very low rates through the BBB. The technique enables brain penetration by redesigning biological drugs into monoclonal antibody fusion proteins (IgG fusion proteins). Research to evaluate the efficacy of this technique is being conducted in mouse models of neurological disorders, including Parkinson's disease, stroke, Alzheimer's disease, and lysosome storage disorders [7].

- Pro-drug bioconversion strategies: This technique consists of developing pro-drug compounds (also called proagents), which are therapeutically inactive agents that can cross the BBB and enter into the brain parenchyma. Upon reaching the target site, these compounds undergo enzymatic and/or chemical transformations and modify their structure, resulting in a biologically active form that is capable of exerting the desired pharmacological effect [12].

- Nanoparticle-based technologies: This technology is primarily based on the use of nanoscale technology for drug release in the brain; the delivery system uses a variety of nanoscale drug delivery platforms, including primarily lipid and polymer-based nanoparticles (NPs) [13]. Studies have shown the potential of NPs as effective drug carriers. SFor example, a study tested the effectiveness of laronidase surface-functionalized lipid-core nanocapsules for the treatment of MPS I; another study loaded arylsulfatase B onto poly(butyl cyanoacrylate) NPs to affect neurological manifestations such as spinal cord compression in MPS VI by delivery of the therapeutic enzyme across the BBB; a third study in two murine models of MPS I and MPS II aimed at assessing the g7-NP brain delivery capacity using a model drug (Albumin-fluorescein isothiocyanate conjugate) [14-16].

- Gene therapy: This technique consists of transferring recombinant DNA with therapeutic function directly into the cells of specific organs [17]. It is a promising solution for neurodegenerative conditions where the neuropathology has spread throughout the entire brain, thus requiring a global CNS gene delivery for effective treatment. Two types of applications of gene therapy are possible: ‘ex vivo’, which involves the collection of target cells, treatment with genetic engineering techniques, and reinjection into the patient; and ‘in vivo’, which is the delivery of a gene directly into the body through a suitable vector such as a plasmid or a non-pathogenic viral vector [retrovirus, adenovirus, adeno-associated virus (AAV)]. Extensive studies of intravenous vector administration performed in newborn mice models of MPS I and MPS VII have shown encouraging results [18]. In another study, the use of systemic delivery AAV vectors in murine models of MPS I, IIIA, IIIB, and VI has demonstrated a reduction of the corresponding substrate in the CNS [19].

- Intracerebral gene therapy: This technique involves direct viral gene delivery into the brain parenchyma or ventricular system. A variety of non-neuronal viral vectors have been studied for CNS gene transfer in vivo in the brain of MPS I, MPS IIIA, MPS IIIB, and MPS VII mouse models via AAV, adenovirus, and lentivirus. The results of phase I/II clinical trials carried out to evaluate the feasibility and safety of brain injection of AAV vectors for MPS IIIA and IIIB suggest that intraparenchymal delivery may be a realistic option for neuropathic MPS [20].

- Intranasal drug delivery: This technique allows rapid delivery of therapeutic molecules directly to the CNS within minutes by bypassing the BBB via a neural pathway connecting the nasal mucosa and brain [21]. Lipid-based NPs have been studied for intranasal drug delivery and this non-invasive strategic approach has been used to evaluate the therapeutic efficacy of neurological symptoms in MPS I disease. In laboratory experiments in mice, intranasal administration of an α-L-iduronidase-encoding AAV serotype 9 (AAV9) vector resulted in the diffusion of the enzyme to deeper areas of the brain and related reduction of tissue GAG storage materials in the brain [22].

Studies on MPS III are actively underway

In MPS IIIA patients, these include a phase IIb study involving intrathecal rhHNS [9], intravenous delivery of a chemically modified sulfamidase in MPS IIIA mice [28], a phase II/III study involving AAV10, and a phase I/II study involving AAV9. In MPS IIIB patients, a phase I/II study involving tralesinidase Alf, a phase II/III study involving anakinra (kineret), and a phase I/II study involving AAV9 and AAV5 are ongoing.