Impact of the Combined Treatment of Liposomed Polyphenols With G04CB02 on the ALS Patients
Condition: Amyotrophic Lateral Sclerosis
MeSH terms: Motor Neuron Disease; Amyotrophic Lateral Sclerosis
Study type: Interventional
Phase: Phase 2

Summary: 
      Amyotrophic lateral sclerosis (ALS) is a disease of an inflammatory nature, which causes
      progressive muscle weakness associated with cognitive and behavioural disorders.
      Pathogenically, it is characterised by loss of oxidative control, excitotoxicity due to
      excess glutamate and intestinal dysbiosis. In the absence of curative treatment, the aim of
      the study is to assess the impact at a clinical level of the combination of liposomed
      polyphenols to improve their effectiveness, with the drug G04CB02 which shows great anti-ALS
      properties by Molecular Topology methodology. A prospective, longitudinal, mixed, analytical,
      experimental and double-blind study is proposed, with a population sample of 60 patients
      distributed randomly in 30 patients in the intervention group who will receive treatment for
      4 months, and 30 patients in the control group who will receive a placebo for the same
      period. The assessment will be at time 0, and at 2 months and 4 months after treatment, with
      functional, cognitive and behavioural tests, and of the state of inflammation and oxidation;
      and at time 0 and 4 months, of the intestinal microbiota.
    

Detailed description: 
      Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of an
      inflammatory nature among those affecting motor neurons, with a life expectancy of 3 to 5
      years. It is characterised by the loss of motor neurons, and can be of the bulbar type when
      the pathology begins to affect the motor neurons located in the spinal bulb, or of the
      medullary type when it begins with a loss of strength and weakness in the extremities. Both
      types eventually lead to an affectation of both motor neurons that results in progressive
      paralysis of the voluntary muscles until the patient dies. In addition, the pathology
      presents cognitive and behavioural alterations. Specifically, deficits have been described in
      verbal fluency, memory, emotional processing or social cognition, which appear to be mainly
      associated with hypoperfusion of the prefrontal area or hypometabolism.

      Pathogenically, ALS is characterised by an alteration in mitochondrial energy use at a
      neuronal level, mainly linked to a lower activity of the enzymes of the electron transport
      chain in the spinal cord. This alteration is a consequence of loss of oxidative control,
      excessive generation of oxidative free radicals, accumulation of neurofilaments, and
      excitotoxicity linked to an increase in the neurotransmitter glutamate.

      In this respect, it has been suggested that bacterial dysbiosis, related to cognitive and
      behavioural worsening, could also contribute to this adverse neuroinflammatory state, having
      been associated with a greater risk of suffering from neurodegenerative diseases.
      Specifically in ALS, a variation in intestinal microbial composition has recently been
      observed, with an increased abundance of E. coli and enterobacteria, and a low abundance of
      total yeast, in patients suffering from ALS; and lower levels of non-butyrate producing
      bacteria needed to maintain the integrity of the intestinal barrier, immune competition and
      energy metabolism. In contrast, increased Akkermansia muciniphila has been associated with
      higher levels of nicotinamide and improved disease symptoms in the animal model of the
      disease.

      This evidence, associated with the lack of medical treatment to cure the disease, makes it
      necessary to look for new therapeutic alternatives of a non-pharmacological nature. These
      include the administration of effective antioxidants, which reverse the high oxidative stress
      and inflammation characteristic of the disease. This type of treatment (specifically the
      association of the antioxidants Pterostilbene and Nicotinamide riboside) has already been
      applied by our research group to patients with ALS, achieving significant clinical
      improvements such as: greater functional capacity, greater respiratory capacity, increased
      muscle strength and electrical activity in the upper and lower limbs, as well as an increase
      in the percentage of skeletal muscle associated with fat loss. In this sense, several
      polyphenols have also been tested in animal models, among which the activity shown by
      Resveratrol stands out, with a high antioxidant power and great neuroprotective capacity,
      which is associated with an increase in the expression and activation of SIRT1 and AMPK in
      the ventral part of the spinal cord after its administration. Both mediators promoted the
      normalization of autophage flow and, more importantly, increased mitochondrial biogenesis in
      SOD1-G93A mice. However, their beneficial effects are strongly limited by their low
      availability. This limitation can be overcome by administering Resveratrol and its natural
      analogues, incorporated in liposomes or nanoparticles, as this is the best option for
      guaranteeing stability and bioavailability, after administration and absorption of the
      antioxidant.

      Moreover, the effects of the polyphenol Curcumin have already been studied in ALS. In a paper
      by Chico et al, its effects were studied in ALS patients at doses of 600mg/day for 6 months.
      In this study they found that Curcumin generated a slight slowdown in the progression of the
      disease, improving aerobic metabolism and oxidative damage. Furthermore, the use of
      nanobiotechnology with Curcumin (80mg/day) in the treatment of ALS patients obtained positive
      results showing that nanocurcumin is safe and could improve the probability of survival as an
      additional treatment in these patients, especially those with existing bulbar symptoms. In
      short, the use of both antioxidants in liposome form improves the bioavailability and effects
      of both, and their liposome combination has already been successfully tested in vivo in
      prostate cancer patients.

      These anti-ALS effects of the two molecules could be complemented by their action in
      improving the microbiota. To obtain the bioactive products of Curcumin, biotransformation by
      the human intestinal microflora is necessary; in a bidirectional manner, it has been
      demonstrated that Curcumin has beneficial effects on the intestinal microbiota by increasing
      the number of bacterial families such as: Prevotellaceae, Bifidobacterium, Lactobacilli,
      Bacteroidaceae and Rikenellaceae, and reducing the number of pro-inflammatory bacterial
      families such as: Enterobacteria and Enterococci. With regard to Resveratrol, as occurs with
      Curcumin, the intestinal microflora contributes to its metabolism; and also stands out in the
      increased production of anti-inflammatory bacteria of the Lactobacillus or Bifidobacterium
      genera. In addition, it has been found to increase levels of the bacterium Akkermansia
      Muciniphila, which is associated with an improvement in the prognosis of the disease.

      Finally, the use of these two antioxidants in ALS would be combined synergistically by
      repositioning G04CB02, a drug selected after a molecular topology scan of more than 30,000
      drugs from two databases: CMC and Drugbank. It is currently marketed for the treatment of
      different pathologies, such as benign prostatic hyperplasia and androgenic alopecia.
      According to the in silico studies based on Molecular Topology carried out by Dr. Gálvez's
      team, a very promising anti-ALS effect has been identified for G04CB02, linked to the TDP-43
      RNA mediator, among others. Drug design using molecular topology consists of applying
      topological descriptors to identify and describe, using a specific mathematical pattern,
      molecules and/or drugs related to a specific disease, in this case ALS. Using molecules with
      proven anti-ALS activity (Edaravone and Riluzole) and the TDP-43 RNA mediator, this
      mathematical pattern was identified and the databases mentioned above were traced with the
      aim of identifying drugs that share the same pattern and therefore have potential anti-ALS
      activity. In addition, considering the current shortage of effective treatments for ALS,
      other mathematical patterns related to anti-inflammatory, antioxidant, neuroprotective and
      analgesic activity were taken into account when selecting the G04CB02 candidate. To date,
      molecular topology has enabled the identification of new treatments for CNS diseases such as
      Alzheimer's, cancer and very recently SARS-Cov-2, among others.
    

Intervention name(s): Liposomed polyphenols resveratrol and curcumin; Placebo for liposomed resveratrol and curcumin; Isocaloric Diet; G04CB02; Placebo microcrystalline methylcellulose
Intervention type(s): Dietary Supplement; Other; Dietary Supplement; Drug; Other
Intervention description(s): Combination of resveratrol (75mg) and curcumin (200mg) liposomed; Water with sucrose replacing the liposomed polyphenols; 40% carbohydrates, 40% lipids and 20% proteins; G04CB02, in a single daily dose for 4 months; Placebo replacing G04CB02
Intervention MeSH terms: Curcumin; Resveratrol
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Intervention group: 30 patients will be administered daily the combination of Resveratrol (75mg) and Curcumin (200mg) liposomes with G04CB02 (0.5mg), in a single dose for 4 months.
Control group: 30 patients, who will receive a placebo with the same dosage pattern and for the same period of time. The placebo will consist of water with sucrose replacing the liposomed polyphenols, and a soft capsule of microcrystalline methylcellulose instead of G04CB02. Both the packaging and the capsule format will be identical to those of the treatment administered in the intervention group.
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Supportive Care