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Concept and Objectives

The overall objective of MeuSIX is to perform a multicenter Phase I/II clinical trial to investigate the safety and efficacy of adeno-associated viral (AAV) vector-mediated gene therapy in patients with mucopolysaccharidosis VI (MPS VI).

Description of the disease: MPS VI, also known as Maroteaux-Lamy syndrome, is a severe autosomal recessive lysosomal storage disorder, without CNS involvement, that belongs to the group of mucopolysaccharidoses (MPS). The MPS are caused by defects in lysosomal enzymes resulting in widespread intra- and extra-cellular accumulation of glycosaminoglycans (GAGs).

MPS VI is caused by deficiency of the enzyme arylsulfatase B [ARSB] that results in intralysosomal storage and increased urinary excretion of partially degraded GAGs. The biochemical diagnosis of MPS VI is based on the detection of elevations in urinary dermatan sulfate and is confirmed by reduced ARSB activity in cell extracts. Diagnosis is based on an ARSB enzyme activity below 10% of the lower limit of the normal range in cultured fibroblasts or isolated leukocytes and the presence of clinical findings consistent with MPS VI.

The rate of clinical progression in MPS VI patients varies considerably, generating a spectrum of clinical presentations that ranges from rapidly to slowly progressive disease. Nevertheless, all patients within this spectrum will eventually experience significant morbidity and in most cases early mortality. The classic features of MPS VI include hydrocephalus and spinal cord compression, coarse facial features, corneal clouding, hearing loss, macroglossia, heart valve disease, respiratory difficulties, hepatosplenomegaly, inguinal and abdominal hernias, dwarfism/growth retardation, skeletal dysplasia, and joint stiffness. Growth can be normal for the first few years of life but it is virtually arrested by the age of 6 to 8 years, with a final height ranging from 110 to 140 cm. Restriction of joint movements (elbow, hip, and knee) develops in the first years of life and children assume a crouched stance. Unlike what observed in other MPS, cognitive functions are usually normal in MPS VI.

Enzyme Replacement Therapy (ERT) has limited efficacy on MPS VI: ARSB, like other lysosomal enzymes, is secreted and uses the mannose-6-phosphate receptor (M6PR), present on the plasma and endosomal membranes of most cell types, to be taken up and directed to the lysosomal compartment. Based on this rationale ERT is used to treat MPS VI. ERT with recombinant ARSB (galsulphase, Naglazyme; BioMarin Pharmaceutical Inc, Novato, CA) has been approved by the Food and Drug Administration and the European Medicines Agency, and is currently available in the United States, Europe, and Australia. At the present time, ERT is recommended as therapy for MPS VI and results in long-term reduction of urinary GAGs and improvements in endurance. However, ERT has several limitations. First, rhARSB has a short half-life and requires weekly intravenous infusions that carry a risk of allergic reaction and often require a central venous access which carries risks of sepsis. Second, some organs and tissues are not corrected, likely because of poor vascularization and limited biodistribution of rhARSB. For example in MPS VI patients, ERT failed to ameliorate cardiac function, visual impairment, and bone density while inconsistent improvements have been shown in lung volumes (FEV1 and FVC), obstructive apnea, joint range of motion and stiffness. Third, the cost of ERT is extremely high thus representing a significant burden for the health system and preventing access to therapy to patients from less developed countries.

Gene therapy as a one-in-a-lifetime treatment for MPS VI: Gene therapy has the potential to convert an organ such as liver to a “depot” for sustained systemic release of secreted proteins like ARSB. Vectors derived from the adeno-associated virus (AAV) are considered the safest tool for long-term and efficient gene transfer to liver. This represents the first proof-of-concept in humans that AAV2/8-mediated gene transfer has the potential to convert the liver in to a factory organ for long-term release of therapeutic proteins.

We have investigated the approach in small and large animal models of MPS VI and were able to show that a single intravascular administration of AAV2/8 encoding ARSB results in: i. efficient transduction of MPS VI rat and cat livers; ii. expression of therapeutic ARSB levels for at least 3 years post-injection; iii. significant improvement of biochemical, pathological, and skeletal features in a large animal model of MPS VI.

We are now planning to translate these encouraging pre-clinical results into the clinic and we propose to perform a clinical trial of intravascular administration of AAV2/8 expressing the human ARSB gene in MPS VI patients. As a preliminary step towards this direction, we have received, from both the European Medicines Agency and the US Food and Drug Administration, the Orphan Drug Designations for the use of ARSB encoding AAV2/8 vector by intravascular infusion as a therapy for MPS VI patients. Therefore, we are now very well positioned to move further in the development of a Phase I/II gene therapy clinical trial for MPS VI to investigate the safety and efficacy of a single intravascular administration of the vector AAV2/8 in MPS VI patients.

The MPS VI gene therapy trial we are proposing will be the first gene therapy clinical trial for a metabolic disease using AAV2/8 and may pave the way towards clinical trials for other diseases due to lysosomal enzyme deficiency, and in general for inborn errors of liver metabolism. Indeed, the results from our study will support the strategy of liver engineered by viral vectors as an efficient and safe factory organ for the production and systemic secretion of therapeutic proteins.  Positive results from this clinical study will provide important data to design a pivotal study to support marketing authorization of AAV2/8.TBG.hARSB as a treatment for MPS VI.

To achieve this important goal, we have identified five main milestones, which are the objectives of our proposal:

1) to produce Good Manufacturing Practice (GMP) (clinical-grade) AAV2/8.TBG.hARSB vector for a gene therapy human clinical trial;

2) to perform pre-clinical pharmacological (pharmacodynamics and pharmacokinetics), immunological, and toxicological studies using the GMP AAV2/8.TBG.hARSB vector required to perform a human clinical trial;

3) to design a Phase I/II clinical trial testing the GMP AAV2/8.TBG.hARSB vector in MPS VI patients to generate data in terms of pharmokinetics, pharmacodynamics, safety, and efficacy;

4) to produce and file the documents required to obtain authorizations to perform a Phase I/II clinical trial from the Italian, Turkish and Dutch regulatory agencies;

5) to perform a multicenter Phase I/II clinical trial to investigate the safety and efficacy of AAV2/8.TBG.hARSB gene therapy for MPS VI.

In conclusion, MeuSIX has been designed to investigate the safety and efficacy of intravascular administrations of AAV2/8 in MPS VI patients. Positive results from this Phase I/II study will support the licensure of AAV2/8.TBG.hARSB for the treatment of MPS VI. If successful, this therapeutic strategy may overcome the limitations of ERT, including limited efficacy and the need for multiple intravenous administrations. In addition, the results of this trial may show the clinical potential of AAV2/8-mediated liver gene therapy as a strategy for the treatment of other LSDs or rare diseases requiring sustained systemic release of therapeutic proteins.

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