Gene Therapy:

Preclinical Targets

uniQure has deep expertise in developing gene therapies in diseases of the liver and central nervous system, and has established a partnership with Bristol-Myers Squibb to develop gene therapies in cardiovascular diseases and other targets.

As we focus on advancing our first two potentially transformative gene therapies for hemophilia B and Huntington’s disease, we are looking farther out on the horizon for new, life-changing applications of our expertise and technologies.


Fabry disease

Our new product candidate AMT-190 is a differentiated gene therapy for the treatment of Fabry disease.  Fabry disease is an inherited lysosomal storage disorder caused by a defect in a gene that encodes for a protein called α-galactosidase A (GLA). The GLA protein is an essential enzyme required to breakdown globotriaosylsphingosine (Gb3) and lyso-globotriaosylsphingosine (lyso-Gb3). In patients living with Fabry disease, Gb3 and lyso-Gb3 accumulate in various cells throughout the body causing progressive clinical signs and symptoms of the disease. Current treatment options, which consist of bi-weekly intravenous enzyme replacement therapy, have no therapeutic benefit in patients with advanced renal or cardiac disease. Studies have also shown that a majority of male patients develop antibodies that inhibit the GLA protein and interfere with therapeutic efficacy.

AMT-190 is a one-time, intravenously-administered, AAV5-based gene therapy designed to circumvent GLA antibodies that can inhibit efficacy in Fabry patients. AMT-190 incorporates a modified version of α-N-acetylgalactosaminidase (NAGA), a protein that is structurally similar to the GLA protein but is not recognized by GLA-neutralizing antibodies. As such, AMT-190 has the potential to be a more effective, longer-term treatment of Fabry disease.

Preclinical studies demonstrate proof-of-concept of AMT-190 as a gene therapy candidate for Fabry disease. A one-time administration of AMT-190 could potentially lead to long-term expression of GLA in the liver, kidneys and heart, with no loss of expression due to inhibitors.


Spinocerebellar Ataxia Type 3 (SCA3)

Our new gene therapy candidate AMT-150 is a novel treatment for Spinocerebellar Ataxia Type 3, a central nervous system disorder.

Spinocerebellar Ataxia Type 3 (SCA3), also known as Machado-Joseph disease, is caused by a CAG-repeat expansion in the ATXN3 gene that results in an abnormal form of the protein ataxin-3. People with SCA3 experience brain degeneration that results in movement disorders, rigidity, muscular atrophy and paralysis. There is currently no treatment available that slows the progressive course of this lethal disease.

AMT-150 is a one-time, intrathecally-administered, AAV gene therapy incorporating the Company’s proprietary miQURE™ silencing technology that is designed to halt ataxia in early manifest SCA3 patients.

Preclinical studies show that a single administration of AMT-150 results in sustained expression and efficient processing with on-target engagement. They also show that AMT-150 appears to be safe due to a lack of off-target activity. The Company is currently performing studies in large animals to demonstrate further safety and efficacy.


Cardiovascular disease

In April 2015, uniQure signed a strategic partnership with Bristol-Myers Squibb (view press release) to discover and develop novel gene therapies to treat a range of cardiovascular diseases, initially focused on the one-time treatment of congestive heart failure.

uniQure and our collaboration partner, Bristol-Myers Squibb, completed a heart function proof-of-concept study of the first target, AMT-126 in a pre-clinical animal model of heart failure. The study demonstrated DNA delivery and expression of S100A1 in the myocardium, thereby validating uniQure’s vector delivery platform in the animal model. The data did not show a benefit on heart function at six months, and consequently, the Joint Steering Committee has chosen to discontinue work on S100A1. Bristol-Myers Squibb intends to replace the S100A1 collaboration target with another cardiovascular target. Bristol-Myers Squibb and uniQure will continue working on the other collaboration targets under the collaboration.


Gene therapy cardiovascular sidebar