Cell Regeneration Peptides

A first-in-class approach to stop & reverse cell, tissue and organ degeneration

NWL has developed a class of safe and stable peptidomimetic drugs that can selectively target specific caspases. NWL’s selective caspase inhibition platform comprises different classes of inhibitors selective to specific caspases. The lead compound is NWL-283, a selective inhibitor of Caspase 3, solves many of the problems that other previous pan-caspase inhibitor programs encountered (stability, toxicity, selectivity, and potentially serious-side effects with chronic use). NWL-283 has been designed to not interfere with normal cellular functions by having a mode of action that selectively removes excess caspase-3 from degenerating and stressed cells. Different compounds within this platform can prevent tissue atrophy and degeneration such as muscle atrophy, diabetes, Parkinson’s, Alzheimer’s, and Multiple Sclerosis. At higher doses lead compound NWL-283 can also stop apoptosis that causes the majority of cell death in stroke, spinal cord injury, traumatic brain injury, and myocardial infraction. If proven successful in several of the investigated indications, NWL-283 will be a true blockbuster drug.

Based on the comprehensive preclinical work on NWL-283, NWL is now ready to embark on required GLP studies and then human clinical trials.

NWL-283 Selective Caspase 3 modulator: Cell “Survival” molecules for degenerative diseases and ischemia Stroke
Spinal cord injury
Traumatic brain injury
Multiple Sclerosis (MS)
Parkinson’s disease
Alzheimer’s disease
Myocardial Infarction
Next Step: GLP-Tox
NWL-154 Selective Caspase 6 modulator: Axonal “Survival” molecules for neuronal connections Alzheimer’s disease
Huntington’s disease
Early Preclinical
NWL-149 Selective Caspase 1/4 modulator: for inflammatory-related degenerative diseases Inflammatory/Automminue degenerative diseases, e.g. Multiple Sclerosis (MS), AD, Heart Disease Early Preclinical

Inspired by one of NWL’s main investors, the company embarked in 2007 on custom-designing a drug-based treatment to stop progression – and even reverse the effects – of degenerative diseases, including progressive MS. Studying the mechanisms underlying damage from tissue trauma (the majority of which is not caused by the trauma itself but from apoptotic and other signals released by the cells that die from the trauma or stroke) demonstrated that many of these same processes also occur in degenerative diseases. In this context certain members of the caspase family were selected as targets for a selective inhibitor to prevent tissue atrophy and degeneration. Innovative leaps were made to circumvent the selectivity, toxicity, stability, and long-term use problems due to which previous drug development efforts by major players in this area had failed.

NWL has generated a vast amount of convincing data for NWL-283: In MS (relapsing-remitting and chronic progressive EAE) in vivo models as well as Parkinson’s disease (6-OHDA) in vivo models, NWL-283 completely stopped the progression of the disease and even reversed the effects of paralysis (p<0.001). NWL-283 has been shown to be safe, stable, and is able to cross the blood-brain-barrier in rodents and primates. Its unique mode of action is also expected to reduce tumor re-growth and metastasis.

In the 1990s a key player in degenerative diseases was identified: the caspase family of cysteine proteases. Caspases (Cysteine-dependent aspartate-directed proteases) are involved in a number of cellular functions, with apoptosis (programmed cell death) being the most studied role. Unfortunately the early understanding of these nuclear and cytoplasmic enzymes led to pharmaceutical development in early 2000 that focused solely on inhibiting all caspases and apoptosis without fully understanding the interplay between the different caspases (14 different caspases have been identified so far, of which 11 exist in all human cells) and esp. their other roles in degenerative diseases and cancer. As a result these efforts led to no approved drugs.

However, renewed interest in the field has recently started to emerge (there was a small string of key Nature publications on the subject in 2010 and 20111) as specific caspases – especially caspase 3 – were found to play central roles in degenerative disease progression. Caspases are interestingly the only molecules that have been shown to be involved in virtually all degenerative diseases and their inhibition has shown very significant, almost curative-like effects in many disease models2. These studies have demonstrated that the caspase equilibrium is impaired in degenerative diseases leading to a higher rate of cell death. Caspases are also over-activated in tissue trauma and ischemia resulting in significantly more cell loss than would be necessary in today’s emergency medical care – thus there is a great unmet medical need for a drug that could stop this cell loss from occurring.

Contrary to current beliefs, mice genetically lacking Caspase 3 do not readily form tumors even when tumor formation is attempted to be induced in these mice3 (i.e. these mice are “tumor-resistant”). Other studies have shown that Caspase 3 inhibition slows down tumor re-growth and metastasis4, and lower levels of Caspase 3 translate to better outcomes in human cancer patients5. This is contrary to the results seen with pan-caspase inhibitors (that target numerous caspases simultaneously) where inhibition of multiple or certain combinations of caspases increases tumor risk. A caspase inhibitor thus needs to be selective to a specific safe effector caspase – such as Caspase 3 – to safely treat degenerative diseases, ischemia, and tissue trauma.

1 Burguillos et al., 2011; Calignon et al., 2010; D’Amelio et al., 2011; Huang et al., 2011; Hyman, 2011; Gyrd-Hansen and Meier, 2010.
2 Akpan and Troy, 2012; Bredesen, 2009; Bulat and Widmann, 2009; Burguillos et al., 2011; Calignon et al., 2010; Castro et al., 2010; Chakraborty et al., 2010; D’Amelio et al., 2011; Das et al., 2008; Franchi et al., 2009; Graham et al., 2011; Hyman, 2011; Kokoulina and Rohn, 2010; Li et al., 20008; Merkle et al., 2007; Montaner et al., 2011; Plant et al., 2009; Radziszewska et al., 2009; Rohn and Head, 2008; Rohn and Head, 2009; Rosell et al., 2008; Sairanen et al., 2009; Sareen et al., 2012; Smith et al., 2011; Teschendorf et al., 2008; Troy et al., 2011; Yamada et al., 2010; Venero et al., 2011; Vincent and Mohr, 2007; Xiong et al., 2008.
3 Radziszewska et al., 2009.
4 Gdynia et al., 2007; Gyrd-Hansen and Meier, 2010; Kim et al., 2008; Kim et al., 2008.
5 Huang et al., 2011; Galluzzi et al., 2012; Lauber et al., 2011; Yang et al., 2009.

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