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LEXINGTON, Mass. & AMSTERDAM—uniQure recently hosted its Research & Development Day in New York City, an event at which the company unveiled a number of new adeno-associated virus (AAV) gene therapy approaches. The therapies address a number of different diseases, including hemophilia A, Fabry disease and spinocerebellar ataxia type 3 (SCA3).
SCA3 is a rare, lethal and inherited form of ataxia alternatively known as Machado-Joseph disease, and at present there are no therapies to halt disease progression. This disease results from a CAG-repeat expansion within the ATXN3 gene, which causes the gene to produce an abnormal form of the ataxin-3 protein. SCA3 is characterized by brain degeneration that manifests in movement disorders, rigidity, muscular atrophy and paralysis.
AMT-150 is a single-administration AAV gene therapy administered intrathecally. An in-vitro study using human induced pluripotent stem-derived neurons demonstrated that AMT-150 was capable of lowering the human ataxin-3 protein by 65 percent with no off-target effects. In a proof-of-concept in-vivo study in SCA3 mouse models, AMT-150 reduced toxic ataxin-3 protein by 65 percent in the brain stem after one administration. In non-human primates, the compound was able to “distribute and express a reporter gene at a clinically relevant level in the most degenerated brain regions in SCA3,” a uniQure press release noted.
Melvin Evers, senior scientist at uniQure, tells DDNews that “From other programs, we know that we achieve the highest lowering between two and four months post-treatment due to a combination of time required for maximal transgene expression, and ataxin-3 protein half-life. Likewise, the murine target sequence has one mismatch with the lead candidate’s human ataxin-3 target sequence. Therefore, the observed lowering is an underestimation of the foreseen (non-)human ataxin-3 lowering. We anticipate to achieve between 50 to 75 percent sustained mutant ataxin-3 protein lowering with the lead compound.”
A bit further down the line, in animal studies, is AMT-180, a gene therapy for hemophilia A. The development of inhibitors that neutralize infused Factor VIII activity occurs in roughly 30 percent of patients with hemophilia A. uniQure's AMT-180, an AAV5-based gene therapy that features a proprietary modified Factor IX gene (Super9), has shown the ability in preclinical studies to circumvent FVIII inhibitors. When tested in a proof-of-concept study in hemophilia A mice, Super9 led to clinically relevant FVIII mimetic activity and did not cause hypercoagulability in wild-type mice. In non-human primates, a single dose of AMT-180 led to expression levels associated with FVIII mimetic activity that is expected to be clinically relevant in hemophilia A patients with or without inhibitors.
Rounding out the trio is AMT-190, a differentiated gene therapy for Fabry disease, an inherited lysosomal storage disorder that results from a defective copy of the gene that encodes for the α-galactosidase A (GLA) protein. The GLA protein breaks down globotriaosylsphingosine (Gb3) and lyso-globotriaosylsphingosine (lyso-Gb3), which accumulate in the cells of patients with Fabry disease and lead to progressive symptoms. Compared to the current bi-weekly treatment options, AMT-190 requires a single dose administered intravenously. This gene therapy bypasses GLA antibodies that interfere with efficacy in patients with Fabry disease by incorporating a modified version of α-N-acetylgalactosaminidase (NAGA). NAGA is built similarly to the GLA protein, but it is not recognized by GLA-neutralizing antibodies.
A preclinical proof-of-concept study in mice with Fabry disease found that one dose of AMT-190 led to modified NAGA expression and GLA activity in plasma, and at two and four weeks after dosing, GLA activity led to a 50-percent reduction in lyso-Gb3 levels. Ever notes that with a single dose of AMT-190, “lifetime treatment is expected as no inhibitors will be formed against the transgene, given Fabry patients already have endogenous NAGA expression.”
uniQure's Research & Development Day also featured a look at its miQURE technology, a gene silencing platform “designed to degrade disease-causing genes without off-target toxicity and induce silencing of the entire target organ through secondary exosome-mediated delivery.”
According to Ever, this technology has a number of advantages, including “Sustained therapeutic effect after one-time treatment; no off-target effects; nuclear and cytoplasmic lowering; cross-correction by extracellular spread; and expression from polymerase II promoter for tissue specificity and regulation, thus no saturation of endogenous RNAi machinery.”
“We are very proud of the progress the company has made to deliver extensive preclinical data for these new gene therapy programs that expand our pipeline and further validate uniQure’s potential best-in-class vector delivery platform,” Dr. Sander van Deventer, chief scientific officer at uniQure, commented in a press release. “The addition of these gene therapy candidates for indications in the liver and CNS brings us yet another step closer towards uniQure's goal of delivering transformational medicine to patients suffering from genetic diseases. We look forward to advancing these programs closer to the clinic in 2019.”