Drug discovery and development

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This is blog number 17 in our ‘Symposium Blogathon’ – counting down to the 32^nd International Symposium on ALS/MND. Numbers in bold green type correspond to the code in the abstract book. Click on the number to be redirected to the full abstract (the page may take a minute to load).

Drug discovery can be described as the process of identifying chemical entities that have the potential to become therapeutic agents. For every new drug brought to the market, most estimates suggest that researchers will typically test tens of thousands of compounds looking for drug leads – a chemical compound that shows promise as a treatment for a disease and may lead to the development of a new drug. Lead drug discovery is costly and time-consuming, taking many years and costing potentially hundreds of millions of dollars, even before drug development begins. Even when a lead drug shows promise, compounds often fail in the development stage for reasons that are unpredictable in the lead discovery phase.

Drug development comprises all the activities involved in transforming a compound from drug candidate (the end product of the discovery phase) to a product approved for marketing by the appropriate regulatory authorities – another process that is long and costly.

Before a drug can be tested in clinical trials in people (part of the development process), it must first be examined in a lab to provide an insight into its mechanism – how it is likely to work in the body, its safety, and preliminary effectiveness. These studies can be done in cells in a lab dish (in vitro), in animals (in vivo) or using computer modelling (in silico).

While there is only a limited number of clinical trials, there are many compounds currently being investigated that could have the potential to be developed into treatments for MND. In general, though, only an extremely small proportion of compounds tested in pre-clinical studies get to the final drug approval stage, reflecting the rigorous process that assures only safe and effective drugs are tested in clinical trials and then approved.

It has been proposed that reactivation of endogenous retroviruses (ERVs), specifically human endogenous retrovirus type K (HERV-K), may be a causative factor of MND through interaction with TDP-43 and immune regulators. Could a treatment that reduces levels of HERV-K slow the progression of MND? A phase 2 clinical trial of an anti-retroviral therapy, Triumeq, to target endogenous retrovirus activity showed slower than average decline in patients receiving Triumeq compared to pre-treatment levels, and serum levels of HERV-K were also significantly reduced. However, how Triumeq conveys this benefit and its influence on TDP-43, HERV-K and inflammation is still unknown.

Researchers in Australia have evaluated motor symptoms, TDP-43 proteinopathy and immune response after administration of Triumeq in a TDP-43 mouse model of MND compared to untreated TDP-43 mice. Triumeq was administered to the mice for 15 or 30 days. Prior to treatment, motor strength was measured and again at 15- and 30-days post treatment onset. TDP-43 levels of treated and untreated mice were compared and immune response was also measured. The results, which will be discussed in poster TST-08, provide insight into the mechanisms of action of Triumeq and give a better understanding of antiretroviral treatment to target TDP-43 related pathology in MND, highlighting a potential therapeutic avenue to treat MND.

The accumulation of TDP-43 in the cytoplasm of motor neurones, is seen in the majority of people with MND. There may be therapeutic potential in targeting TARDBP (the gene that codes for TDP-43) and/or the STMN2 gene with antisense oligonucleotides (ASOs) to restore TDP-43 levels to normal and prevent decreased expression of Stathmin-2 – the protein made by the STMN2 gene. Stathmin-2 is a microtubule-associated protein that has a major role in axonal development and repair. The results of this early study will be discussed in poster TST-10.

In a chemical screen to search for targets that can rescue the degeneration of motor neurons grown from cells taken from many people with both familial and sporadic MND, researchers in the USA have discovered that inhibitors of PIKFYVE kinase (responsible for the production of phospholipids, which are one of the key components of the cell membrane and whose principal role is instructional: they interact with proteins), were the most broadly efficient across patient subtypes. They found that PIKFYVE activates a form of autophagy that maintains proteostasis (the process of regulating proteins within the cell) by clearing misfolded proteins including mutated C9orf72 proteins and TDP-43. Suppression of PIKFYVE by ASOs rescues motor neurons from patients with sporadic and familial MND in vitro. In vivo it has shown significant rescue of motor neuron function and survival in animal models of MND. After screening hundreds of candidate ASOs, AS-202 was identified as a development candidate and may offer a promising therapeutic approach for people with sporadic MND (TST-17).

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