Preclinical Targets

uniQure has deep expertise in developing gene therapies in diseases of the liver and central nervous system.

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

Fabry disease is an X-linked genetic disorder resulting from a deficiency of α-galactosidase A (α-gal or GLA). The current standard of care for Fabry disease is bi-weekly infusions of enzyme replacement therapy, a treatment that has limited effectiveness in many patients due to poor cross-correction, which hampers clearance of substrates in the target organs, in particular the kidney and the heart. 

In September 2020, uniQure selected a lead gene therapy candidate AMT-191 for the treatment of Fabry disease to advance into IND-enabling studies. The lead candidate is a one-time administered AAV5 gene therapy incorporating an α-galactosidase A (GLA) transgene. In preclinical studies comparing multiple product candidates, including constructs incorporating a modified alpha-N-acetylgalactosaminidase transgene (modNAGA), AMT-191 demonstrated the most robust and sustained increases in GLA activity and subsequent functional improvement.


Spinocerebellar Ataxia Type 3 (SCA3)

Our 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, with a lack of off-target activity. In SCA3 mouse models, AMT-150 was shown to dose-dependently reduce ataxin-3 protein aggregation resulting in prevention of neuropathology. The Company is currently performing IND-enabling studies in large animals to demonstrate safety and efficacy. 


Temporal Lobe Epilepsy (TLE) 

In July 2021 uniQure acquired Corlieve Therapeutics and its lead program, now known as AMT-260, to treat temporal lobe epilepsy, the most common form of focal epilepsy.

Our gene therapy candidate AMT-260 employs miRNA silencing technology to target suppression of aberrantly expressed kainate receptors in the hippocampus of patients with temporal lobe epilepsy (TLE). TLE affects approximately 1.3 million people in the U.S. and Europe alone, of which approximately 800,000 patients are unable to adequately control acute seizures with currently approved anti-epileptic therapies. Patients with refractory TLE experience increased morbidity, excess mortality, and poor quality of life.


Alzheimer's disease

In June 2021, Introduced new candidate AMT-240, a new treatment modality for autosomal dominant Alzheimer’s disease. 

Alzheimer’s disease is the most prevalent neurodegenerative disease, causing dementia and subsequent gradual loss of ability to function with disease progression. Apolipoprotein E (APOE) has been shown to be a key player in the pathogenesis of Alzheimer’s disease.  APOE consists of 3 major isoforms that are structurally and functionally different. The APOE4 isoform is found to be the largest risk factor to develop Alzheimer’s. In contrast to the toxic properties of APOE4, clinical case studies have shown the protective role of other APOE variants.

AMT-240 is a one-time gene therapy using uniQure's miQURE gene-silencing technology to silence the toxic APOE variant, in combination with overexpressing a protective APOE variant as treatment for autosomal dominant Alzheimer’s disease patients.


Parkinson's disease

uniQure is developing gene therapy candidate AMT-210, targeting alpha-synuclein as a treatment for Parkinson’s disease.

Parkinson’s disease is caused by progressive neurodegeneration, manifesting itself with progressive motor deterioration and debilitating non-motor symptoms. It is the second most common neurodegenerative disorder after Alzheimer’s disease, and no disease-modifying therapies are available.

The hallmark of Parkinson’s disease is the presence of toxic alpha-synuclein aggregates, affecting dopaminergic circuits.  AMT-210 is a one-time, brain-targeting AAV gene therapy incorporating uniQure's miQURE gene silencing technology. It is designed to halt misfolded alpha-synuclein and subsequent fibril formation in familial and sporadic Parkinson’s disease patients.


Amyotrophic lateral sclerosis (ALS)

Our gene therapy candidate AMT-161 utilizes miQURE gene silencing technology to target toxic C9ORF72 as a treatment for amyotrophic lateral sclerosis (ALS). 

ALS is caused by degeneration of upper and lower motor neurons, resulting in muscle weakness and atrophy. This rapid progressive loss of motor neurons typically starts at mid-life and median survival from disease manifestation is no more than two to four years.

The most prevalent genetic defect causing ALS is a G4C2 hexanucleotide repeat expansion in the C9ORF72 gene, which acquires toxic properties resulting in degeneration starting in motor neurons in the spinal cord.  AMT-161 is a one-time, intrathecally-administered AAV gene therapy using the miQURE silencing technology to target repeat-expanded C9ORF72 to lower toxic RNA aggregates and prevent dipeptide protein formation. 


Cardiovascular and other diseases

In May 2015, uniQure signed a strategic partnership with Bristol-Myers Squibb (BMS) to discover and develop novel gene therapies. Bristol-Myers Squibb and uniQure have an agreement that provides BMS with exclusive access to uniQure’s gene therapy technology platform for multiple targets in cardiovascular diseases as well as the potential for target-exclusive collaboration in other disease areas. In total, the companies may collaborate on four targets.

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