Currently available treatments for amyotrophic lateral sclerosis (ALS) are unable to delay its progression. Endoplasmic reticulum (ER) stress is an early pathogenic event underlying motoneurons (MNs) vulnerability and denervation in ALS, caused by an accumulation of misfolded proteins. In conditions of prolonged ER stress, cell death occurs.Thus in ALS, MNs gradually die, and the brain loses the ability to initiate and control voluntary muscle movement (e.g. chewing, walking, talking, breathing). As a result, ALS patients face rapid muscular deterioration that rapidly leads to disability and culminates in death 3–5 years after diagnosis. Neurotrophic factors (NTFs) are promising candidates for treating neurodegenerative diseases such as ALS. However, no NTF-based therapy has been successful in clinical trials to date, as they show (i) no statistically significant modification in disease progression in patients, (ii) no effect on survival times, and (iii) severe side effects that limit dosing in patients8. Importantly, as NTFs are unable to cross the blood-brain barrier (BBB), they must be administered directly into the brain or intrathecal space - highly invasive procedures that put patients at risk of tissue damage, iatrogenic pain syndrome, toxicity, or the formation of tumours9. As a result, NTFs are only administered to late-stage patients. Thus, there is a clear need to develop effective, easy-to-administer and cost-effective ALS treatments.
I have discovered that MANF fragment is transported to the Brain, so it can be subcutaneously administered, is safe, economical, and has neurorestorative effects. In addition, my group has already demonstrated that MANF fragment has protective and restorative effects on motoneurons:
A clear improvement in motor coordination and a 2-week increase in survival and a protection of spinal cord motoneurons was observed after 4-week chronic subcutaneous MANF fragment administration in SOD1-G93A ALS mice.
Importantly, no off-target effects or in vivo side-effects were identified. Moreover, the selectivity of MANF fragment has the potential to be easily tailored to target indications beyond ALS to a myriad of neurodegenerative diseases with common mechanisms
In this project the effects of MANF fragment were validated in cell and animal models of ALS and we also performed an IP landscape analysis and establish freedom-to-operate (FTO) and analyzed the market structure. We additionally familiarized ourselves to competitive strategies that are being developed for the treatment of ALS
