Novel Small Molecules with Neuroprotective Potential in ALS: A 'Fly-to-Human' Approach

We aim to discover novel therapeutic targets and strategies for amyotrophic lateral sclerosis (ALS) that will ultimately lead to the development of new drugs to treat and/or stop the disease progression. Our approach is to, first, screen for novel compounds that mitigate ALS phenotypes such as locomotor defects in simple yet disease-relevant fruit fly models of motor neuron degeneration. This is advantageous because it is rapid and in vivo. Next, we validate the successful compounds in patient-derived motor neurons from both familial and sporadic ALS cases. This combined approach offers effective, disease-relevant identification of novel compounds that exhibit neuroprotective potential. Notably, this approach, referred to as phenotypic screening, has the advantage of letting the disease models inform the researchers about 'what works' without making any assumption about the pathways that go awry in degenerating neurons. As a team, we have the capability to strategically synthesize novel small molecules based on feedback from how they perform in fruit flies and patient-derived motor neuron screens. This combined, integrative approach increases confidence in the compounds selected for further study and therapeutic development in the future.

Broadening the impact of our studies is the use of multiple models of genetically modified fruit flies and motor neurons derived from both familial and sporadic cases of ALS; thus, our findings have the potential to benefit multiple types of ALS and improve the outcome for a significant fraction of the patient population.

In summary, the outcomes that we aim for include: (1) discovery of novel lead compounds that mitigate ALS phenotypes in vivo, in fruit flies, and in patient-derived motor neurons; (2) cast a broad net for discovering compounds that mitigate multiple types of ALS including sporadic cases; (3) identify the molecular targets and pathways that our novel, neuroprotective compounds engage with to mitigate ALS. Ultimately, these novel compounds, their molecular targets, and pathways they modulate will pave the way for much needed therapeutic strategies that improve motor neuron function and survival.

We are committed and have the expertise to advance the successful lead compounds into therapeutics. Since the validations are performed in patient-derived motor neurons, we expect to be able to advance to safety studies immediately following the completion of this project.