The PATrOL™ platform acts by preventing the translation of mutant proteins and is thus able to address a multitude of genetic diseases
Rare genetic diseases are often particularly severe, debilitating or fatal, with 30% of affected children dying before their fifth birthday*.
While these conditions are rare and individually affect small populations, collectively they are estimated to affect between 5-10% of the global population (NORD). Unfortunately, 95% of these hundreds of millions of patients who are affected by these devastating rare genetic diseases have no available treatment options*.
The collective population of people with these rare genetic diseases stand to benefit profoundly from the emergence of a scalable treatment platform that allows for rapid drug development and can address these conditions with a unified and scalable approach. The breadth of the PATrOL™ platform gives NeuBase the ability to tackle a multitude of these rare genetic diseases efficiently and cohesively. Our initial focus will be on neurological repeat expansion disorders.
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Repeat expansion disorders
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Polyglutamine CAG Repeats
Huntington’s disease (HD) is a rare, dominantly -inherited, fatal neurodegenerative disorder, with symptoms such as uncontrolled movements, cognitive impairments and emotional disturbances worsening over time.
HD is caused by the toxic aggregation of mutant huntingtin protein, leading to progressive neuron loss in the brain. It is one of at least 30 known repeat expansion disorders, or diseases caused by the repetition of simple DNA sequences. In the case of HD, the wildtype huntingtin gene has a region in which a three-base sequence, CAG, is repeated many times. When CAG is repeated 35 or fewer times in this region, the resulting protein behaves normally. When CAG is repeated more than 36 times in this region, the resulting protein becomes toxic and causes HD.
Current therapies for patients with HD can only manage individual symptoms. There is no approved therapy that has been shown to delay or halt disease progression.
PATrOL-enabled NT0100 is currently in preclinical development for the treatment of HD. NeuBase is conducting preclinical studies with the goal of filing and IND for NT0100 in the second half of 2020.
Myotonic dystrophy type 1 (DM1) is a rare, autosomal dominant disorder characterized by progressive muscle wasting and weakness. While commonly described as a muscle disease, it can also affect the eyes, heart and brain.
DM1 is a repeat expansion disorder caused by an abnormally expanded section of the DMPK gene, which plays a role in cellular communications within heart, brain and muscle cells. The mutated DMPK gene produces an expanded version of DMPK mRNA, which then forms clumps inside cells due to its abnormal length. These clumps then interfere with the function of many other proteins, leading to the many symptoms associated with this disease.
There is currently no cure for DM1, and treatment is usually targeted at managing symptoms as much as possible.
PATrOL-enabled NT0200 is currently in preclinical development for the treatment of DM1. The PATrOL platform is uniquely positioned to treat DM due to the technology’s ability to target secondary RNA structures, thereby shortening the mutated RNA and inhibiting the production of the clumps known to interfere with normal cellular function.
Dominant genetic disorders
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LRRK2 & SNCA
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Due to the advantages of the PATrOL™ platform, NeuBase is well positioned to address dominant and recessive diseases. In addition to the ability of PATrOL-enabled therapies to cross the blood brain barrier, the engineered oligonucleotides can self-assemble across a target transcript and concatenate, increasing steric selectivity and inhibition of translation. This allows the therapies to selectively target the expansion repeats in the mutant protein while leaving the wildtype protein intact and functional.
Using its PATrOL™ technology, NeuBase has plans to address additional repeat expansion disorders such as myotonic dystrophy as well as other genetic disorders and oncogenic mutations in the future.