Ataxia-telangiectasia: Treating Mitochondrial Dysfunction With Nicotinamide Riboside

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 mg/kg/day 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

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 serine/threonine 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 2A/B clinical trial exploring the efficacy and tolerability of C7 in AT patients (https://classic.clinicaltrials.gov/NCT04513002).

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 oxidation/reduction 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 NAD+/SIRT1 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 25mg/kg/day 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.

Eligibility Criteria:
Inclusion Criteria:

Participants who meet all of the following criteria are eligible for enrolment:

* Patients of either sex, of any age, with a confirmed diagnosis of A-T,
* Patients who are able to undertake the study procedures,
* Families who are able to comply with the protocol for its duration and who provide informed patient assent and consent signed and dated by parent/legal guardian or adult participant according to local regulations.

Exclusion Criteria:

Participants who meet any of these criteria are not eligible for enrolment:

* Patients whose parents/legal guardians are not able to provide consent
* Patients who have been in another randomised clinical intervention trial where the use of investigational medicinal product within 3 months or 5 half-lives, whichever is longer, before study enrolment
* Taking off label mediations or nutritional supplements that the PI consider would impact participant's safe participation.
* Patients who are pregnant and/or lactating, planning a pregnancy during the study. Contraception must be used for sexually active male and female participants
* Liver enzymes (alanine aminotransferase \[ALT\]/aspartate aminotransferase \[AST\]) or total bilirubin \> 2 x the upper limit of normal at the time of screening.
* Renal insufficiency as defined by estimated glomerular filtration rate (eGFR) \< 30 mL/min/1.73m2 at the screening visit.
* Any comorbid medical condition that in the assessment of the PI that would impact participant's safe participation (e.g. active cancer requiring treatment)
* Evidence of dysphagia that places subject at risk of aspiration if orally fed.