A highly promising Compound has formed the basis for a new pharmaceutical company. This company is Called Atricode and is based on compounds that have been researched at University of Southern California to treat and cure Myotonic Dystrophy. Sita Reddy’s Lab has been instrumental in moving these potential treatments (MDI16) for Myotonic Dystrophy. The lab and company has recently been awarded a $90,000 grant through a competitive process. More about the grant:

2012 USC Ideas Empowered Program Grant: $90,000

Atricode is developing treatments for rare diseases. The lead indication, Myotonic Dystrophy Type 1 (DM1,) is a devastating genetic multisystem disorder with no available treatment or cure. This team identified highly potent and selective small molecule leads that rescue DM1 pathology in patient myoblasts and in DM1 mouse models. The team joined forces with experienced entrepreneurs to form a start-up company that moves the drug candidates towards the clinic. The drug candidate could be the first therapy to treat this devastating disorder and the Ideas Empowered funds are critical for the selection of the lead candidate for clinical development and to support fundraising efforts.

Team Members:

— Sita Reddy, Keck School of Medicine of USC
— Lucio Comai, Keck School of Medicine of USC
— Donald Dixon, Keck School of Medicine of USC
— Nouri Neamati, USC School of Pharmacy
— Adam Simpson, Atricode
— Bob Baltera, Atricode
— Brian Varnum, C3 Jian
— Raju Mohan, Atricode

The Company seems to be in a fundraising mode and It looks very promising. Myotonic Dystrophy has a huge financial potential. In other Blog Posts I have explored that this potential may be as high as 2.5 BILLION dollars. Because of its complexity and the number of organ systems that are involved there is a high probability that this drug will have some success in treating the many facets of the disease. This compound seems especially promising as it seems to transcend the blood brain barrier. Patients and patient advocacy groups maintain that the CNS effects are among the most debilitating to the patient population

Summary of some studies on MDI16

Lucio Comai, Ph.D. Development of small molecule therapeutics with optimized blood-brain barrier permeability for DM1
Myotonic dystrophy 1 (DM1) is an autosomal dominant disorder, with a frequency of 1 in 8000 people, for which there is no cure or treatment (1). DM1 results from the expansion of a CTG repeat sequence in the 3’ untranslated region of the DMPK gene (2). This defect results in the expression of toxic DMPK RNAs encoding expanded CUG repeat (CUGexp) sequences. CUGexp sequester the RNA splice regulator MBNL1 to form CUGexp-MBNL1 aggregates in DM1 nuclei (3,4). Aberrant sequestration of MBNL1 results in RNA splice defects and alterations in RNA steady-state levels (5). CUGexp is a key DM1 therapeutic target as antisense oligonucleotide (AON) degradation of CUGexp results in the reversion of DM1 pathology (6). Peptides that bind CUGexp and prevent binding of MBNL1 also show efficacy in reversal of DM1 features (7). As implementation of AON and peptide based therapies face challenges, we developed a primary high throughput screen (HTS) and a secondary hit validation assay to identify small molecules that specifically alter the biology of CUGexp RNAs without affecting the normal DMPK transcript. This novel strategy allowed the identification of a highly potent and selective small molecule (MDI16) that effectively and specifically rescues DM1
pathology in both patient myoblasts and in mouse models that demonstrate DM1 pathology in skeletal muscle. As CNS pathology is a very serious feature of DM1 (1), it is important that the final lead compound show good CNS uptake properties. Therefore we propose to test and optimize blood brain barrier permeability and CNS efficacy of leads in this application.

HIGH THROUGHPUT SCREEN FOR MYOTONIC DYSTROPHY TYPE 1

Neamati Nouri
University Of Southern Californiacity: Los Angeles    country: United States (us)

Grant 1R03MH095544-01 from Roadmap Initiative, Office Of The Director

Abstract: Myotonic dystrophy (DM1) is the most common adult onset muscular dystrophy in humans. Currently, there is no cure or an FDA approved drug for DM1 and related diseases. The molecular basis of DM1 is the expansion of a CTG-repeat sequence in the 3´ untranslated region of the protein kinase gene, DMPK. This defect results in the expression of mutant DMPK RNAs encoding expanded CUG repeats (CUGexp) that form large intra nuclear RNA-protein complexes or foci. Expression of CUGexp RNAs leads to abnormal RNA splicing, which in turn has been linked to the development of key features of DM1 pathology. We hypothesize that small molecules that degrade or disperse CUGexp RNAs in DM1 cells can re-establish normal splice patterns and reverse DM1 pathology. To test this hypothesis, we developed a primary HTS and a secondary hit validation assay to identify small-molecules that alter the biology of CUGexp RNAs without affecting the normal transcript. Our in house library was developed using a robust machine learning chemoinformatics platform and consists of 40,000 highly diverse small-molecules representing a library of over a million compounds. An initial screen of 2,500 small molecules from this library resulted in the identification of a potent lead compound, MDI16, which reverses aberrant RNA splice patterns in both DM1 patient myoblasts and in the HSALR mouse model for DM1. In a concerted effort to identify other potent lead compounds we propose the following Aim 1. Implement primary HTS and the secondary hit validation assay in the MLPCN center. Aim 2. Test hits in tertiary cell-based assays to identify highly potent molecules that reverse four key cellular DM1 phenotypes. Aim 3. Characterize the selectivity and toxicity of lead compounds and identify their mechanism of action at the cellular level using a set of cell-based assays developed in the lab. Aim 4. In conjunction with the MLPCN center, we will refine the chemical structure of lead compounds reiteratively to optimize pharmacological properties and establish structure-activity relationships. Lay Summary Myotonic dystrophy type 1 is a neuromuscular disorder for which there is no treatment or cure. Over the past few years exciting strides in our understanding of the mechanistic basis of this disorder have been made. Thus the field is poised to make a major breakthrough and develop a drug for this disorder. We have developed a sensitive high throughput screen (HTS) to identify compounds that cure or ameliorate pathologies associated with myotonic dystrophy. Currently we have discovered potent molecules, which rescue DM1 pathology in both DM1 patient myoblasts and in DM1 mouse models. As our screens have been proven to identify potent molecules that rescue DM1 pathology, in this application we propose to identify other lead compounds by screening the MLPCN chemical library with our HTS. Identification of multiple leads will greatly improve the probability of a small molecule therapy for DM1

Keywords: 3` Untranslated Regions; Adult; Affect; Antisense Oligonucleotides; base; Binding (Molecular Function); Biological Assay; Biology; Cells; Chemical Structure; Consult; Data; Defect; Development; Disease; Ectopic Expression; FDA approved; Genes; high throughput screening; Housing; Human; improved; In Vitro; in vivo; Lead; Libraries; Link; Machine Learning; Mediating; Molecular; mouse model; Muscular Dystrophies; mutant; Myoblasts; Myotonic Dystrophy; Neuromuscular Diseases; Nuclear RNA; Pathology; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Probability; Property; protein complex; Protein Family; Protein Kinase; Protein Kinase C Alpha; RNA; RNA Splicing; Screening procedure; Series; small molecule; small molecule libraries; Structure-Activity Relationship; System; Testing; Therapeutic; therapeutic target; Toxic effect; Transcript; transcription factor; Validation

Relevance: Lay Summary Myotonic dystrophy type 1 is a neuromuscular disorder for which there is no treatment or cure. Over the past few years exciting strides in our understanding of the mechanistic basis of this disorder have been made. Thus the field is poised to make a major breakthrough and develop a drug for this disorder. We have developed a sensitive high throughput screen (HTS) to identify compounds that cure or ameliorate pathologies associated with myotonic dystrophy. Currently we have discovered potent molecules, which rescue DM1 pathology in both DM1 patient myoblasts and in DM1 mouse models. As our screens have been proven to identify potent molecules that rescue DM1 pathology, in this application we propose to identify other lead compounds by screening the MLPCN chemical library with our HTS. Identification of multiple leads will greatly improve the probability of a small molecule therapy for DM1

Project start date: 2011-07-22

Project end date: 2013-06-30

Budget start date: 22-JUL-2011

Budget end date: 30-JUN-2012

1R03MH095544-01 (2011): $40750