Amyotrophic Lateral Sclerosis (ALS)

                                   

ALS, sometimes called Lou Gehrig's disease, is a rapidly progressive, invariably fatal neurological disease that attacks the nerve cells (neurons) responsible for controlling voluntary muscles (muscle action we are able to control, such as those in the arms, legs, and face).



                                   
                                   

The disease belongs to a group of disorders known as motor neuron diseases, which are characterized by the gradual degeneration and death of motor neurons. More than 12,000 people in the U.S. have a definite diagnosis of ALS, for a prevalence of 3.9 cases per 100,000 persons in the U.S. general population, according to a report on data from the National ALS Registry. ALS is more common among white males, non-Hispanics, and persons aged 60–69 years, but younger and older people also can develop the disease. Men are affected more often than women. ALS causes weakness with a wide range of disabilities. Eventually, all muscles under voluntary control are affected, and individuals lose their strength and the ability to move their arms, legs, and body. When muscles in the diaphragm and chest wall fail, people lose the ability to breathe without ventilatory support.

Most people with ALS die from respiratory failure, usually within 3 to 5 years from the onset of symptoms. However, about 10 percent of those with ALS survive for 10 or more years.

                                   

Our Therapeutic Approach

                                   

Thera’s technology platform is uniquely positioned to pursue a two-technology therapeutic approach to the disease.


                                   
                                   

The complex pathogenesis of ALS presents features that impact differently the clinical presentation leading to heterogeneity of the patient population. The role of SOD1 is established in familial ALS but it’s unclear to what extent impacts the development of the disease in patients with sporadic ALS.

Our SMRT lead compounds, SYN1 and SYN2, act through a mechanism of effect independent from directly targeting SOD1-induced damage and engaging other mechanisms that are known to be involved in the expression of the disease.

Our sd-rxRNA® technology platform can impact the disease from a genetic standpoint, silencing SOD1 but also other proteins (like TDP-43) that seems to be involved in ALS pathogenesis.

There are potential synergies between our small molecule and sd-rxRNA® technologies that may allow us to target the multiple factors involved in the pathogenesis of ALS with an impactful disease-modifying and potentially curative effect.

                                   
                                   

Rilutek, the only approved treatment for ALS, only marginally slows down the progression of ALS but does not restore motor neuron functionality. The successful development of Thera's technology could potentially lead to a therapeutic drug(s) capable to restore muscle movement in patients with ALS.


                                   

SMRT Lead Candidates

                                   

Our lead candidates entering translational stage for ALS belong to the original and unique class of small molecules able to mitigate three key pathogenic mechanisms of the disease.

Based on our in vitro and in vivo data we strongly believe that both SYN1 and SYN2 are effective in ALS independently (or at least not uniquely) from their effect on SOD1 dysfunction. They showed to: a) protect motor neurons against oxidative stress, b) induce neuritic/axonal regeneration sustaining axonal well-being, and c) activate compensatory mechanisms to counteract the neurotrophic deficit responsible for motoneurons degeneration and the consequent clinical manifestations of ALS.

SYN1 and SYN2 were tested independently and in separate blinded efficacy experiments in the ALS animal model. Both compounds, administered at disease onset proved to be equally effective in the disease modification of ALS in symptomatic animals with mutant SOD1 (high copy SOD1-G93A mice) and phenotyped for a stage equivalent to a patient’s moderate presentation of the disease.
They showed to be effective through the simultaneous mitigation of a) oxidative toxicity, b) cell dysfunction, and c) neurotransmission deficit, most likely independently from the impairment caused exclusively by the SOD1 deficit.

Based on our in vitro and in vivo data we strongly believe that both SYN1 and SYN2 are effective in ALS independently (or at least not uniquely) from their effect on SOD1 dysfunction.

                                   
                                   

This multifactorial effect of our compounds translated in the animal model through the:
1. symptomatic improvement: reduced weight loss (over 50%) and improved neurologic scores (over 65%)

• most likely correlated to both improved mitochondrial function and restored protein activity/function

2. delayed disease progression: mice spent more time in milder stages of disease (cumulated, higher than 60%)
• as a function of both improved cell functioning and neurotransmission

3. increased survival rate: first and only evidence, to date, of over 50% increase in survival in SOD1 G93A animals treated at disease onset
• likely resulting from the concerting of the antioxidant, protein folding/antiaggregant, and neurite repair/regeneration effects.