The accumulation of toxic protein clumps is a crucial contributor to cell damage in people with ALS (TDP-43), Alzheimer's disease (beta-amyloid), or Parkinson's disease (alpha-synuclein). These aggregates are composed of abnormal proteins that fail to acquire their standard three-dimensional shape.
In the case of ALS, the clusters of TDP-43 are also located in the cytosol, i.e. where the proteins are produced, before being folded up in the ER and then sent to their place of use by the Golgi apparatus. After shipment, TDP-43 should be in the nucleus.
Arimoclomol is an oral therapy that increases the production of heat shock response proteins (HSPs), which help misfolded proteins to their normal shape. HSPs also direct the removal of abnormal proteins when refolding is not possible.
One would therefore think that if ALS is primarily a problem with folding proteins, therapies that help misfolded proteins acquire their typical configuration should slow the progression of ALS. This has been tested with Arimoclomol. For once a clinical trial would have been launched on a drug that seemed to have a good chance of succeeding (oddly drug targets in most clinical trials in neurodegenerative diseases seem to be based on non-scientific criteria).
Arimoclomol was evaluated in a previous Phase 2/3 clinical trial (NCT00706147) in 36 patients with rapidly worsening ALS due to SOD1 mutations. The choice to select SOD1 patients is quite curious. There are countless SOD1 mutations, with consequences ranging from extremely rapid deterioration (a few months) to extremely slow deterioration (death after 10 years). There are therefore probably multiple mechanisms of action at work.
On the other hand, SOD1 mutations are only present in 5% of ALS cases. But SOD1 mutations were the first mutations discovered in ALS and are by far the most studied for 30 years, yet without significant progress being recorded.
Although this clinical trial did not show statistically significant results, the company Orphazyme managed to find funding for a phase III trial. The Phase 3 ORARIALS-01 trial (NCT03491462) studied arimoclomol in 245 adults with ALS. This clinical trial did not achieve its objectives. Arimoclomol did not prolong the life of patients or even delay the progression of disability in people with the disease. In other words, it was a spectacular failure, like almost all clinical trials in ALS.
Although I am neither a doctor nor a scientist, this made me think that the premises for rationale of arimoclomol in ALS were false. Personally, since that time, I am convinced that ALS is due to a cellular stress response that does not stop and which therefore destroys not only neurons but also muscle cells.
Indeed, the response to cellular stress consists of an almost total shutdown of the cell, this shutdown cannot be permanent. This stop explains very well the loss of muscle mass (which scientists explain by the death of motor neurons, while this loss occurs before motor neurons death).
From this perspective (very personal), any action aimed at increasing the energy expenditure of the cell (it takes energy to fold proteins), is doomed to failure.
Yet the scientists behind arimoclomol in 2004, seem to be back at the lab table. This time they are no longer interested in SOD1 mutations but in VCP mutations. VCP mutations are very rare, less than 1% of ALS cases. They conducted a study of arimoclomol in mice with a mutation in valosin-containing protein (VCP) that causes both ALS and FTD in patients.
Similar to studies of arimoclomol in SOD1 mice, enhancement of the heat shock response ameliorated the ALS/FTD-like phenotype in the spinal cord and brain of VCP mutant mice. Arimoclomol prevents neuronal loss in it. Additionally, in human cell models, the authors demonstrate improvements in pathology in VCP mutant patient fibroblasts and iPSC-derived motor neurons.
The scientists suggest that targeting HSP may have therapeutic potential, not only in non-SOD1 ALS, but also for the treatment of FTD.
Errare humanum perseverare diabolicum