Ignite Creation Date:
2024-05-06 @ 8:17 PM
Last Modification Date:
2024-10-26 @ 3:24 PM
Study NCT ID:
NCT06324877
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-04-18
First Post:
2024-03-15
Brief Title:
Ataxia-telangiectasia Treating Mitochondrial Dysfunction With Nicotinamide Riboside
Sponsor:
The University of Queensland
Organization:
The University of Queensland
Study Overview
Official Title:
Single Arm Open-label Clinical Trial in Ataxia-telangiectasia to Test the Effects of Nicotinamide Riboside on Ataxia Scales Immune Function and Neurofilament Light Chain
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ATNAD
Brief Summary:
Study design Single arm open-label clinical trial in ataxia-telangiectasia to test the effects of nicotinamide riboside on ataxia scales immune function and neurofilament light chain Study population 6-10 patients with Ataxia-Telangiectasia Dose Nicotinamide riboside 25 mgkgday in 3 equal divided doses
Primary endpoint Scales for assessment and rating of ataxia SARA and International Cooperative Ataxia Rating Scale ICARS Improvement of at least ½ standard deviation in key clinical scales which includes either a significant improvement in total combined scores from the SARA and ICARS scales and or b significant improvements any aspects of the SARA and ICARS scales individually especially pertaining to Postural and gait improvements Improved syllable speed and articulation Improved fine motor skills
Secondary endpoints Serum analysis of neurofilament light chain Nfl Type 1 Interferon INFs epigenetic signature
Primary endpoint Scales for assessment and rating of ataxia SARA and International Cooperative Ataxia Rating Scale ICARS Improvement of at least ½ standard deviation in key clinical scales which includes either a significant improvement in total combined scores from the SARA and ICARS scales and or b significant improvements any aspects of the SARA and ICARS scales individually especially pertaining to Postural and gait improvements Improved syllable speed and articulation Improved fine motor skills
Secondary endpoints Serum analysis of neurofilament light chain Nfl Type 1 Interferon INFs epigenetic signature
Detailed Description:
Ataxia Telangiectasia A-T is a rare genetic progressive life-limiting neuro-degenerative condition affecting a variety of body systems resulting in ataxia immune deficiency respiratory complications and a predisposition to cancer Currently there is no cure for A-T
Over the years a number of small clinical trials using steroids antioxidants and anti-inflammatory agents have had little success The disease natural history is relentless leading to early death A-T generates a significant disease burden for the individuals their extended families and on health care resources With palliative care being the only current option for families a treatment trial for A-T meets an unmet need Our group previously demonstrated compelling evidence of reversible mitochondrial dysfunction and preventable cell death in A-T patient cells and the beneficial effects of heptanoate C7 the primary metabolite of triheptanoin C7 corrects a defect in endoplasmic reticulum ER-mitochondrial signalling in A-T cells and has great potential for application in treating patients C7 has been utilised with efficacy and safety over the last 15 years for inborn errors of metabolism IEM such as long chain fatty acid defects LC-FAOD
A-T is due to a genetic defect that results in a defective serinethreonine protein kinase known as ATM Normally ATM plays a central role in protecting the genome against damage It is increasingly evident that ATM protects cells against oxidative stress This protein is also present outside the nucleus where it is activated by oxidative stress through a separate mechanism from DNA damage providing an explanation why anti-oxidants have a protective role in A-T cells in culture and in animal models From these and other studies it is evident that mitochondrial abnormalities characterise ATM and it has been suggested that A-T should be considered at least in part as a mitochondrial disease
We have added substance to that claim by showing that ATM-deficient B3 cells are exquisitely sensitive to inhibition of glycolysis by glucose deprivation compared to controls HBEC We have also shown this increased sensitivity to nutrient deprivation for primary epithelial cells from patients and in immortalised patient cells We demonstrated that this was caused by defective assembly of the VDAC1-GRP75-IP3R1 calcium channel and less ER-mitochondria contact points as determined by transmission electron microscopy This in turn resulted in reduced calcium release from the ER and less transfer to mitochondria providing further evidence for mitochondrial dysfunction in A-T cells We have recently completed a Phase 2AB clinical trial exploring the efficacy and tolerability of C7 in AT patients httpsclassicclinicaltrialsgovNCT04513002
Nicotinamide adenine dinucleotide NAD is an essential cofactor for many cellular enzymes including those involved in mitochondrial biogenesis and maintenance Nicotinamide adenine dinucleotide exists in two forms including an oxidized NAD and a reduced NADH form and plays a key role in intermediary metabolism as obligatory partner in numerous oxidationreduction reactions The cellular pool of NAD and NADH is tightly regulated through a careful balance between its biosynthesis and its breakdown by NAD-consuming enzymes NAD deficiency plays a role in disease mechanisms underlying DNA repair disorders Mitochondrial damage and NAD depletion are key features in ataxia telangiectasia
ATM-deficient mice have neuronal NAD deficiency in particular in the cerebellum
Fang et al have demonstrated that mitochondrial dysfunction in ATM deficiency is linked to NADSIRT1 inhibition NAD replenishment significantly extends lifespan and improves health span in both ATM worms and mice through mitophagy and DNA repair Treatments that replenish intracellular NAD reduce the severity of A-T neuropathology normalize neuromuscular function delay memory loss and extend lifespan in both animal models Mechanistically treatments that increase intracellular NAD also stimulate neuronal DNA repair and improve mitochondrial quality via mitophagy
Immune deficiency is common in AT with most patients have humoral and cellular immune defects comprising immunoglobulin-A deficiency immunoglobulin-G2 and immunoglobulin-G deficiency and lymphopenia with low numbers of total and naive CD4 T cells About 10 of patients with classic ataxia-telangiectasia present with hypogammaglobulinaemia with normal or raised immunoglobulin-M levels and follow a severe disease course Recognition of foreign or misplaced nucleic acids is one of the principal modes by which the immune system detects pathogenic entities When cytosolic DNA is sensed a signal is relayed via the cGAS-STING pathway
ATM deficient cells display elevated levels of INF- induced proteins a feature also reported in sera of A-T patients A double knockout of ATM and STING genes in mice attenuated autoinflammatory phenotypes which was further decreased when the cGAS gene is also deleted in these mice Inhibition of the cGAS-STING pathway ameliorates the premature senescence phenotype in AT brain organoids Similar inflammatory manifestations are seen in patients with STING-associated vasculopathy in infancy which is an autosomal dominant type 1 interferonopathy
Two groups have explored Nicotinamide Riboside NR supplementation in small groups of A-T patients via single arm open label access proof-of-concept clinical trials Both have demonstrated improvements in validated ataxia scales Improvements in immunoglobulin-G IgG levels were observed no alterations were noted in NFlc Improvements were lost in the wash out period NR was well tolerated with no reported adverse events
This is a single arm open-label clinical trial in ataxia-telangiectasia to test the effects of nicotinamide riboside on ataxia scales immune function and neurofilament light chain
Dose will be via oral capsule supplementation at 25mgkgday divided into 3 doses max 300mgs 3 times per day Dosing will occur via 3 equal doses 3 times a day
Primary efficacy endpoint Improvement of at least ½ standard deviation in key clinical scales which includes either a significant improvement in total combined scores from the SARA and ICARS scales and or b significant improvements any aspects of the SARA and ICARS scales individually especially pertaining to Postural and gait improvements Improved syllable speed and articulation Improved fine motor skills
Secondary endpoints include Serum analysis of neurofilament light chain Nfl Type 1 Interferon INFs epigenetic signature specifically the cGAS-STING pathway
Safety endpoints Treatment-related adverse events Routine haematology and biochemical analyses Paediatric Epilepsy Side Effects Questionnaire PESQ Regular clinical assessments
Over the years a number of small clinical trials using steroids antioxidants and anti-inflammatory agents have had little success The disease natural history is relentless leading to early death A-T generates a significant disease burden for the individuals their extended families and on health care resources With palliative care being the only current option for families a treatment trial for A-T meets an unmet need Our group previously demonstrated compelling evidence of reversible mitochondrial dysfunction and preventable cell death in A-T patient cells and the beneficial effects of heptanoate C7 the primary metabolite of triheptanoin C7 corrects a defect in endoplasmic reticulum ER-mitochondrial signalling in A-T cells and has great potential for application in treating patients C7 has been utilised with efficacy and safety over the last 15 years for inborn errors of metabolism IEM such as long chain fatty acid defects LC-FAOD
A-T is due to a genetic defect that results in a defective serinethreonine protein kinase known as ATM Normally ATM plays a central role in protecting the genome against damage It is increasingly evident that ATM protects cells against oxidative stress This protein is also present outside the nucleus where it is activated by oxidative stress through a separate mechanism from DNA damage providing an explanation why anti-oxidants have a protective role in A-T cells in culture and in animal models From these and other studies it is evident that mitochondrial abnormalities characterise ATM and it has been suggested that A-T should be considered at least in part as a mitochondrial disease
We have added substance to that claim by showing that ATM-deficient B3 cells are exquisitely sensitive to inhibition of glycolysis by glucose deprivation compared to controls HBEC We have also shown this increased sensitivity to nutrient deprivation for primary epithelial cells from patients and in immortalised patient cells We demonstrated that this was caused by defective assembly of the VDAC1-GRP75-IP3R1 calcium channel and less ER-mitochondria contact points as determined by transmission electron microscopy This in turn resulted in reduced calcium release from the ER and less transfer to mitochondria providing further evidence for mitochondrial dysfunction in A-T cells We have recently completed a Phase 2AB clinical trial exploring the efficacy and tolerability of C7 in AT patients httpsclassicclinicaltrialsgovNCT04513002
Nicotinamide adenine dinucleotide NAD is an essential cofactor for many cellular enzymes including those involved in mitochondrial biogenesis and maintenance Nicotinamide adenine dinucleotide exists in two forms including an oxidized NAD and a reduced NADH form and plays a key role in intermediary metabolism as obligatory partner in numerous oxidationreduction reactions The cellular pool of NAD and NADH is tightly regulated through a careful balance between its biosynthesis and its breakdown by NAD-consuming enzymes NAD deficiency plays a role in disease mechanisms underlying DNA repair disorders Mitochondrial damage and NAD depletion are key features in ataxia telangiectasia
ATM-deficient mice have neuronal NAD deficiency in particular in the cerebellum
Fang et al have demonstrated that mitochondrial dysfunction in ATM deficiency is linked to NADSIRT1 inhibition NAD replenishment significantly extends lifespan and improves health span in both ATM worms and mice through mitophagy and DNA repair Treatments that replenish intracellular NAD reduce the severity of A-T neuropathology normalize neuromuscular function delay memory loss and extend lifespan in both animal models Mechanistically treatments that increase intracellular NAD also stimulate neuronal DNA repair and improve mitochondrial quality via mitophagy
Immune deficiency is common in AT with most patients have humoral and cellular immune defects comprising immunoglobulin-A deficiency immunoglobulin-G2 and immunoglobulin-G deficiency and lymphopenia with low numbers of total and naive CD4 T cells About 10 of patients with classic ataxia-telangiectasia present with hypogammaglobulinaemia with normal or raised immunoglobulin-M levels and follow a severe disease course Recognition of foreign or misplaced nucleic acids is one of the principal modes by which the immune system detects pathogenic entities When cytosolic DNA is sensed a signal is relayed via the cGAS-STING pathway
ATM deficient cells display elevated levels of INF- induced proteins a feature also reported in sera of A-T patients A double knockout of ATM and STING genes in mice attenuated autoinflammatory phenotypes which was further decreased when the cGAS gene is also deleted in these mice Inhibition of the cGAS-STING pathway ameliorates the premature senescence phenotype in AT brain organoids Similar inflammatory manifestations are seen in patients with STING-associated vasculopathy in infancy which is an autosomal dominant type 1 interferonopathy
Two groups have explored Nicotinamide Riboside NR supplementation in small groups of A-T patients via single arm open label access proof-of-concept clinical trials Both have demonstrated improvements in validated ataxia scales Improvements in immunoglobulin-G IgG levels were observed no alterations were noted in NFlc Improvements were lost in the wash out period NR was well tolerated with no reported adverse events
This is a single arm open-label clinical trial in ataxia-telangiectasia to test the effects of nicotinamide riboside on ataxia scales immune function and neurofilament light chain
Dose will be via oral capsule supplementation at 25mgkgday divided into 3 doses max 300mgs 3 times per day Dosing will occur via 3 equal doses 3 times a day
Primary efficacy endpoint Improvement of at least ½ standard deviation in key clinical scales which includes either a significant improvement in total combined scores from the SARA and ICARS scales and or b significant improvements any aspects of the SARA and ICARS scales individually especially pertaining to Postural and gait improvements Improved syllable speed and articulation Improved fine motor skills
Secondary endpoints include Serum analysis of neurofilament light chain Nfl Type 1 Interferon INFs epigenetic signature specifically the cGAS-STING pathway
Safety endpoints Treatment-related adverse events Routine haematology and biochemical analyses Paediatric Epilepsy Side Effects Questionnaire PESQ Regular clinical assessments
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None