News - A-T: Scientific and Medical Information

A Miss for Steroid-Toting Red Blood Cells in Ataxia Telangiectasia

Quince Therapeutics doses first subject in Ataxia-Telangiectasia trial

The company anticipates reporting topline results from the Phase III NEAT trial in the second half of next year.

Quince Therapeutics has dosed the first subject in its Phase III NEAT clinical trial of EryDex for the treatment of Ataxia-Telangiectasia (A-T), an inherited neurodegenerative and immunodeficiency disorder.

EryDex consists of dexamethasone sodium phosphate (DSP) encapsulated within the red blood cells of the patient.

The global, multicentre, double-blind, randomised, placebo-controlled trial will analyse the neurological effects of EryDex in A-T patients.

Conducted under a Special Protocol Assessment (SPA) agreement with the US Food and Drug Administration (FDA), the trial aims to enrol approximately 86 subjects aged six to nine years (primary analysis population) and nearly 20 people aged ten years or above.

Trial subjects will be categorised into a 1:1 ratio to receive either EryDex or a placebo, with the treatment regimen involving six infusions given every 21 to 30 days.

ChromaDex wins orphan designation for rare ataxia drug

The company will be filing an IND for nicotinamide riboside chloride (NRC), which has received both orphan and rare pediatric designations.

Justine RaJune 7, 2024

ChromaDex has announced that its treatment candidate nicotinamide riboside chloride (NRC) for the rare disease ataxia telangiectasia, has been granted US Food and Drug Administration (FDA) orphan drug and rare paediatric disease status.

The Los Angeles, California-based dietary supplement and food ingredient company has set plans in motion to file an FDA investigational new drug (IND) for NRC in this indication. As per the 7 June press release, the potential clinical studies will be led by ChromaDex scientific advisor Dr. Vilhelm Bohr.

Ataxia telangiectasia is a rare, inherited, progressive childhood disorder for which symptoms manifest neurologically and immunologically. The disease impacts a part of the brain that regulates motor function, with affected children subsequently exhibiting progressive difficulty with movement coordination and gait (ataxia), impaired eye coordination (oculomotor apraxia), and involuntary movement (choreoathetosis). There are no existing FDA-approved drugs for the treatment of this condition.

ChromaDex is not the only player in the ataxia telangiectasia treatment space. Earlier this week, San Francisco, California-based biotech Quince Therapeutics was awarded an FDA fast track designation for its candidate EryDex. The drug-device treatment is being developed using autologous intracellular drug encapsulation (AIDE) technology and administers the glucocorticoid agonist dexamethasone sodium phosphate into a patient’s red blood cells.

EryDex is currently being evaluated in the Phase III NEAT study (NCT06193200). The trial was initially put on a partial hold, which was lifted in October 2023. The clinical hold was removed after the agency requested additional information on the plastics used in the single-use EryKit which is integral to the treatment. Quince also made other changes that ensured that the commercial version of EryKit complied with European regulations.

Nanopore Long-Read Sequencing Facilitates Diagnosis of Atypical Ataxia-Telangiectasia

April 25, 2024

By Isabella Ciccone, MPH

A case study of a 52-year-old Korean woman revealed the potential of Nanopore long-read sequencing in diagnosing atypical late-onset ataxia-telangiectasia.

In a case study newly published in Neurology Genetics, Nanopore long-read sequencing confirmed the diagnosis of a 52-year-old Korean woman with atypical late-onset ataxia-telangiectasia (AT) characterized by extrapyramidal symptoms with a very slow progression.¹ This report highlights the utility of Nanopore long-read sequencing in phasing variant haplotypes, which may be beneficial for the diagnosis of autosomal recessive disorders especially for those cases without parental samples.

The patient, the second child of 3 in her family, presented a worsening tremor that initiated 5 years prior. At the age of 7 years, the patient had slower handwriting compared with peers and intermittently had difficulty controlling the left hand when washing her face between 9 and 10 years of age. Later, at the age of 13, intermittent bilateral action tremors started, and the symptoms were maintained into her late teens. In her early 20s, intermittent gait disturbances began while action tremor in the hands remained stable, not significantly impeding daily life until jerky head tremors worsened in her late 40s.

Top Clinical Takeaways

Nanopore sequencing may offer valuable insights into atypical presentations of genetic disorders, aiding accurate diagnosis.
Haplotype phasing through long-read sequencing can resolve complex genetic variations, especially in cases without parental samples.
Advancements like amplification-free sequencing using CRISPR/Cas9 enrichment show promise for more direct and less biased genetic analysis in the future.

“Our case was notable because of the patient exhibiting dystonia and dystonic tremor with slow progression as the primary symptoms rather than ataxia. In addition, the patient maintained an independent gait even in her early 50s. These relatively mild clinical features might result from the residual activity in the hypomorphic missense variant, as previously reported,” senior author Han-Joon Kim, MD, PhD, a neurologist and movement specialist at Seoul National University Hospital, and colleagues wrote.¹

Neurologic examination reported dystonia in the face, hand, and trunk in addition to cervical dystonia at 52 years of age during the patient’s first visit. Researchers reported dystonic postural tremors in both of the patients’ hands and suspected a saccadic pursuit during the extraocular movement examination and noted ocular telangiectasia. Investigators did not observe limb dysmetria in the finger-to-nose and heel-to-shin tests for cerebellar function. The patient had a normal base with no difficulty in walking but showed instability during turning. She performed 4 to 5 steps in the tandem gait test and could walk independently. Notably, cognitive function was revealed as normal, and routine blood tests as well as a brain imaging study produced normal results, but the authors noted an increased level of α-fetoprotein.

All told, the patient had a family history of similar symptoms in her older sister, aged 54 years, who experienced tremor in her right hand beginning in her early 20s and progressively worsened as she got older, but remained significantly less severe than the proband. The sister reported involuntary elevation of the right shoulder and difficulty handwriting because of involuntary flexion of the right wrist since adolescence. During neurological examination of the sister, investigators reported mild dysarthria; head tremor; cervical dystonia; and kinetic, intention, and dystonic postural tremors in both hands, notably worse in the right side. In the cerebellar function tests, the sister showed normal performance and had no definite evidence of telangiectasia. Authors reported a detection of elevated α-fetoprotein level of 108 ng/mL despite other blood tests producing normal results, and a diagnosis of breast cancer was noted from 5 years prior.

In a targeted panel sequencing performed in the proband which included 29 hereditary dystonia–related genes, investigators identified 2 heterozygous variants in the ATM gene: c.6040G>T, p.Glu2014Ter, and c.6154G>A, p.Glu2052Lys. The authors noted difficulty in determining the allelic origin of the variants without parental sampling because of the proband’s decreased father, thus, investigators conducted PCR amplification using primers containing these 2 variants and sequenced them using Nanopore long-read sequencing.

The long-read sequencing aligned with the human reference genome hg38 using minimap2² and provided adequate coverage on both variants, which were set apart by 213 base pairs. Haplotype analysis using WhatsHap³ and visual inspection through the Integrative Genomic Viewer established the allele positions of the variants in trans, which confirmed the molecular diagnosis. Additional familial evaluations using Sanger sequencing in the proband’s siblings showed the same pathogenic variants in the older sister and carrier status of the p.Glu2052Lys variant in the other sibling, the younger brother.

“Although the detection of a single heterozygous allele in siblings would have been a robust indicator of the trans effect of the 2 variants, our approach using Nanopore sequencing provided direct and clear haplotype-resolved information for the 2 ATM gene variants,” Kim et al noted.¹ “In addition, while we conducted PCR amplification before sequencing, a noteworthy development is the potential use of amplification-free sequencing. This method, which involves CRISPR/Cas9 enrichment, could offer a more direct and less biased approach. It is particularly effective for assessing haplotype-resolved single-nucleotide variants, structural variations, and CpG methylation.”

REFERENCES
1. Jin B, Yoon JG, Kim A, Moon J, Kim HJ. Late-Onset Ataxia-Telangiectasia Presenting With Dystonia and Tremor. Neurol Genet. 2024;10(2):e200141. Published 2024 April 2. doi: 10.1212/NXG.0000000000200141
2. Li H. Minimap2: pairwise alignment for nucleotide sequences. Bioinformatics. 2018;34(18):3094-3100. doi:10.1093/bioinformatics/bty191
3. Martin M, Ebert P, Marschall T. Read-Based Phasing and Analysis of Phased Variants with WhatsHap. Methods Mol Biol. 2023;2590:127-138. doi:10.1007/978-1-0716-2819-5_8

IBEC and AEFAT join forces against ataxia telangiectasia

Today, the event “Advances in Ataxia Telangiectasia” took place, organized by the Institute of Bioengineering of Catalonia (IBEC) in collaboration with AEFAT, the Spanish ataxia-telangiectasia family association. The gathering brought together patients’ families, researchers, and clinicians to explore the latest advancements in the research and the clinical management of ataxia telangiectasia.

The event “Advances in Ataxia Telangiectasia” took place today, organized by the Institute of Bioengineering of Catalonia (IBEC) in collaboration with AEFAT, the Spanish ataxia-telangiectasia family association, which brings together families affected by ataxia telangiectasia (AT) in Spain, a rare disease that affects at least 40 children and young people in the country.

The meeting, held at the Barcelona Science Park (PCB), gathered patients’ families, researchers, and clinicians with the aim of informing about the research projects recently awarded by AEFAT. It provided a space for reflection to delve into the latest advances in the clinical management of ataxia telangiectasia.

IBEC is committed to collaborating with patients through patient associations to be able to study different rare diseases.
Teresa Sanchis

The day began with a small aperitif and a welcome to the attendees by Teresa Sanchis, Head of Strategy at IBEC, who gave an overview of the research carried out at the center and the initiatives to communicate it to society. “IBEC is committed to collaborating with patients through patient associations to be able to study different rare diseases,” said Sanchis.

Next, it was the turn of Núria Montserrat Pulido, who played a key role as a link between IBEC and AEFAT, leading the organization of the conference. Her position as a principal investigator at IBEC and beneficiary of one of the research projects funded by AEFAT has been the basis of this collaboration. The Montserrat project, entitled “Modelling Ataxia Telangiectasia pathogenesis and therapeutics using human pluripotent stem cells and genetic engineering,” aims to develop organoids from patients’ cells that allow gene editing processes to be tested for different mutations and create a platform for drug testing.

When this project ends, our goal is to make the tools developed available to others, allowing them to use and improve them.
Núria Montserrat

In the words of Núria Montserrat: “When this project ends, our goal is to make the tools developed available to others, allowing them to use and improve them. Our goal is to contribute to the constant progress in research into ataxia telangiectasia and similar diseases, ensuring that the information obtained is available to patient associations.”

The conference continued with the intervention of other researchers who presented the work they carry out within the research projects of AEFAT. Among them are Marc Güell, Principal Investigator of the Translational Synthetic Biology group at Pompeu Fabra University (UPF), and Roberto Bilbao, scientific director of the Basque Biobank, Basque Foundation for Health Innovation and Research (Bioef).

The event was also attended by Jordi Surrallés, director of the Research Institute of the Hospital de la Santa Creu i Sant Pau, and Alejandra Darling, pediatric neurologist at SJD Barcelona Children’s Hospital, who provided the clinical vision.

Finally, the day concluded with the emotional testimonials from some of those present, sharing their personal stories with ataxia telangiectasia and expressing gratitude for the research work carried out. After the closing ceremony, attendees had the opportunity to visit the IBEC facilities to learn about the laboratories where Núria Montserrat’s project will be conducted.

This event exemplifies IBEC’s commitment to working closely with patient associations, promoting research projects focused on their real needs. This comprehensive approach not only strengthens the connection between scientific research and the affected community but also creates a valuable context for the development of innovative solutions and effective therapies.

Organoids to study ataxia telangiectasia

Núria Montserrat Pulido, principal investigator at IBEC, will lead a project to study Ataxia telangiectasia thanks to funding from AEFAT, the Spanish ataxia-telangiectasia family association. The idea of the project is to obtain cells with the patient mutations, develop organoids, explore the possibility of gene editing processes for different mutations and create a platform for drug testing.

IBEC joins Aefat, the association uniting families affected by ataxia telangiectasia in Spain, on its commitment for researching this rare disease that impacts at least 40 children and young individuals in the country. The collaboration is though the project titled “Modelling Ataxia Telangiectasia pathogenesis and therapeutics using human pluripotent stem cells and genetic engineering”, led by Núria Montserrat Pulido, ICREA research professor, and principal investigator of the Pluripotency for organ regeneration group at IBEC.

Montserrat’s project is one of the two selected by the Scientific Committee of the Aefat in its second international call for research projects to find a cure or treatment for this genetic, neurodegenerative and multisystemic disease, poorly researched, with no cure or treatment.

The project aims to obtain iPSc cells with the patient mutations, develop organoids, explore the possibility of gene editing processes for different mutations and create a platform for drug testing.

As detailed by Núria Montserrat, “our collaborative project aims to establish new cellular models to understand ataxia telangiectasia, caused by mutations in the ATM gene. We will use genetic engineering and cell engineering to generate cells with causal mutations of the disease and, on the other hand, generate different types of cells and tissues affected in these patients. For this second objective, we will establish cultures called organoids, which are cellular systems that we can generate in the laboratory that resemble the organ we want to study.”

The goal, as highlighted by the biologist and researcher, “is to create a cellular platform to study processes that are important during ataxia telangiectasia, and what is also crucial, we will be able to exploit this cellular platform to test vectors and therapeutic compounds that allow us to correct defects in cells and mini-organs created in the laboratory due to the presence of mutations in the ATM gene”. Additionally, “we will incorporate the participation of infrastructure such as the Biomodels and Biobanks Platform of the Carlos III Health Institute, through which we will ensure the incorporation and custody of biological samples from the project. And we have the collaboration of Jordi Surrallés, a doctor in genetics and director of the Research Institute of the Sant Pau Hospital”.

For the efficiency of this project, Aefat has connected the team with international researchers working in the same field and other professionals who have participated in projects financed funded by the charity, such as Marc Güell (Pompeu Fabra University, Barcelona).

The new projects are valued at 150,000 euros each, with a duration of 18-24 months. Aefat’s investment effort has been supported by contributions from associations in other countries, specifically two of the nine that form the A-T Global Alliance, an alliance established in 2020 to advance international research and awareness. The English association Action for A-T and the Australian association BrAshA-T are collaborating in financing these two new projects initiated from Spain.

Boston Children's Hospital lab trying to develop drug to treat boy's deadly rare disease

ASO

By Louisa Moller

January 18, 2024 / 6:33 PM EST / CBS Boston

BOSTON - Dr. Tim Yu refers to the letters of the genetic code as Lego blocks. His lab at Boston Children's Hospital has become known for putting the Legos together just right and using them to develop precision drugs called Antisense Oligonucleotides or ASOs to treat incredibly rare neurological diseases.

"You build them like Lego blocks by hooking up the letters to one another. And, when you put them in the order, in the right string of letters, you can get them to target different parts of the genome," Yu told.

It may sound simple but the development of each ASO is tricky and fraught with risks. Yu should know. His lab has been involved in the development of four since 2017.

"We've been fortunate to develop Antisense Oligonucleotides for four diseases that have never previously been treated," Yu said, "These include Batten Disease in 2017, ataxia telangiectasia in 2020, that same year KCNT1 epilepsy, and then a fourth condition, an inherited form of blindness in collaboration with Colorado, N-Lorem, and others."

Now, Yu and his team are trying to develop an ASO for four-year-old Henry Saladino, a rambunctious toddler who loves his blue block and blowing kisses to his mom. He also suffers from a rare neurological disease called Alternating Hemiplegia of Childhood (AHC) which causes weekly seizures and paralysis which threaten to permanently damage his brain or take his life.

"This disease is cruel, it's brutal, and it can take Henry at any moment without warning," his mother Mary Saladino said.

Last year, scientists at the Northwestern Feinberg School of Medicine were testing ASO candidates in Henry's neurons. Each ASO is made of microscopic synthetic strands of DNA and/or RNA that bind to the genetic mutation that is producing the protein causing Henry's disease.

"An ASO can be used to selectively target that messenger RNA for destruction so that the mutant protein is never made or is at least made in less abundance," said lead researcher Dr. Al George in October. "We have some that are promising. I would say they're not quite where I would like to see them."

The Yu Lab at Children's Hospital took up Henry's case on January 1, just two weeks before his fourth birthday. The move brings Henry's ASO candidates and his neurons to the hospital which has treated him since infancy.

"It is a dream come true for our family for sure. I've been chasing Tim since day one, since we first heard about an ASO," Mary Saladino said.

Yu says he sees promise in the case and urgency.

"If we can solve this in Henry for AHC, then the lessons there will have repercussions for hundreds of other diseases that are similar to this," Yu said, "This is a technically tricky and scientifically tricky case."

One of the challenges for Yu and his team will be that they must design an ASO that knocks down the mutated copy of the gene causing Henry's disease but does little or nothing to the healthy copy of the gene.

And, of the handful of ASO candidates that are showing promise in Henry's neurons, none have gone through toxicology testing in mice and rats which could immediately render them useless.

"Because if they're toxic, that's the end of the line for those and we'll move onto others," Dr. George said.

The price tag for developing a drug for just one or a few patients is daunting, roughly $3 million. The Saladino family has raised about half of that.

Because of the rarity of AHC, Mary says no pharmaceutical company is willing to pick up the risk of the project and the expense.

Even amid uncertainty, Dr. Yu believes the time to tackle this science is now.

"It's the exemplar for the type of case from which we can learn a lot about how this technology works," Dr. Yu said. "And if we can make it work for Henry and kids like Henry, the lessons that we learn from that will allow us to hopefully develop drugs for many other kids with conditions that are like Henry's."

More information on Henry's case can be found at www.forhenryahc.org.

U.S. FDA Partial Clinical Hold Lifted on IND for EryDel’s Lead Phase 3 Asset EryDex for the Treatment of Ataxia-Telangiectasia

September 28, 2023 04:05 PM Eastern Daylight Time

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Quince Therapeutics, Inc. (Nasdaq: QNCX), a biotechnology company focused on acquiring, developing, and commercializing innovative therapeutics that transform patients’ lives, today announced that the U.S. Food and Drug Administration (FDA or the “Agency”) has lifted the partial clinical hold on EryDel S.p.A’s Investigational New Drug (IND) application for its lead Phase 3 asset, EryDex. Pending the closing of Quince’s acquisition of EryDel, Quince intends to advance the global Phase 3 NEAT (Neurologic Effects of EryDex on Subjects with A-T) clinical trial evaluating the safety and efficacy of EryDex for the potential treatment of a rare, fatal pediatric neurological disease, Ataxia-Telangiectasia (A-T). Currently, there are no approved treatments for patients with A-T and the market represents a $1+ billion estimated peak sales opportunity.

Dirk Thye, M.D., Quince’s Chief Executive Officer, said, “We are pleased with the FDA’s decision to lift the partial clinical hold related to EryDel’s lead asset, EryDex. We look forward to completing the clinical and regulatory activities necessary to advance EryDex into the Phase 3 NEAT study – with patient enrollment beginning as soon as the second quarter of 2024. Notably, this pivotal trial will be conducted under a Special Protocol Assessment (SPA) that has already been reviewed with the FDA, which should allow for the submission of a New Drug Application (NDA) following completion of this single study, assuming positive results.”

The Agency had requested additional information on extractables and leachables related to a change in plastics utilized in the EryKit. The change in plastic bags and tubing in the EryKit were implemented in order to be compliant with recent European regulations regarding the type of plastics used in various products. The commercial version of the EryKit treatment consumables is already approved for clinical trial use in Europe.

Quince’s acquisition of EryDel is subject to certain regulatory approvals, including the foreign direct investment screening clearance in Italy, and other closing conditions and is expected to close in the fourth quarter of 2023.

About EryDex and the Phase 3 NEAT Trial

EryDex utilizes a unique drug/device combination that enables a fully automated process at the point of patient care for the autologous intracellular drug encapsulation (AIDE) of dexamethasone sodium phosphate (DSP; a pro-drug) into a patient’s red blood cells. Dexamethasone-loaded red blood cells are then re-infused into the patient, resulting in the circulation of controlled, slow release, low doses of dexamethasone, intended to provide efficacious dosing while avoiding the long-term toxicity typically associated with chronic steroid administration.

The Phase 3 NEAT clinical trial is a double blind, randomized, placebo-controlled, global study in approximately 86 A-T patients aged six to nine years-old – with up to an additional 20 patients aged 10 years or older to potentially expand the label. The study’s primary endpoint will measure neurological function based on a rescored modified International Cooperative Ataxia Rating Scale (RmICARS) from baseline to month six of treatment. NDA submission is currently targeted for the end of 2025, assuming positive Phase 3 study results. EryDex has received orphan drug designation for the treatment of A-T from both the FDA and the European Medicines Agency (EMA).

About Quince Therapeutics

Quince Therapeutics is a biotechnology company focused on acquiring, developing, and commercializing innovative therapeutics that transform the lives of patients suffering from debilitating and rare diseases. For more information, visit www.quincetx.com and follow Quince Therapeutics on LinkedIn and @Quince_Tx on Twitter.

A four-decade disease detective

Shiloh Y

Governor of Queensland Celebrates Ataxia Telangiectasia Clinical Trial

The Ataxia Telangiectasia (A-T) clinic at the Wesley Research Institute recently received a visit from Her Excellency the Honourable Dr Jeanette Young AC PSM, Governor of Queensland. The visit which occured on March 24th was a celebration of the clinic’s work on this treatment trial that has been more than 10 years in the making.

A-T is a rare genetic disorder with an incidence of approximately three in one million births – Approximately 40 children in Australia currently have A-T. Patients with A-T often end up in a wheelchair by the age of ten and have a life expectancy of 25 years.

This genetic disorder leads to ataxia; the inability to walk, talk and use fine motor skills because of the neurological impairment. A-T patients also suffer from cystic-fibrosis-like lung disease due to immunodeficiency as well as cancer accounting for a high death rate

The symptoms of A-T are described as the ‘worst parts’ of cerebral palsy, cystic fibrosis and muscular dystrophy with a high risk of cancer and lung disease. There is unfortunately no effective therapy for this illness.

This clinical trial has investigated the use of Triheptanoin, a dietary fat supplement which has the potential to boost energy metabolism and significantly improve neurological symptoms. This treatment trial has given families of patients the hope that they are able to have their children for longer by slowing down the progression of the disease.

As the clinic officially drew to a close last Friday the 31st of March, A-T families came together to receive an update from lead investigator, Professor David Coman – on what is hoped to be achieved and to provide the families with data analysis timelines, as well as future projects.

Thanks to the dedication of the A-T participants (such as Daisy and Grace, pictured) and their families over the past year – without their ongoing commitment to this trial, none of this would have been possible.

Dr Matthew Lynch was also awarded the Dr Kate Sinclair BrAshA-T Research Fellowship Award. This award recognises Dr Lynch’s outstanding contribution to the A-T clinic and his ongoing efforts toward the treatment trial.

The visit from Her Excellency was a testament to the crucial work being done at the A-T clinic here at Wesley Research Institute. The clinic’s researchers and staff are committed to finding effective treatments for A-T and providing support to the families impacted by the disease.

Data collection and analysis are currently underway, as families eagerly await the results. Further details will be coming soon.

Acasti reports results from ataxia telangiectasia therapy trial

The PK bridging study assessed the PK, safety, and bioavailability of GTX-102 given as an oral spray in healthy volunteers.

December 29, 2022

Acasti Pharma has reported preliminary topline results from the pharmacokinetic (PK) bridging study of its drug candidate GTX-102 to treat ataxia telangiectasia (A-T).

The randomised, open-label, crossover study Phase I PK bridging study was designed to assess the PK, safety, and bioavailability of GTX-102 given as an oral spray compared to intramuscular (IM) betamethasone and to betamethasone oral solution (OS) in healthy volunteers.

Its primary objective was to assess and characterise the GTX-102’s PK profile as an oral spray.

The company stated that 48 healthy adult participants were enrolled in this eight-sequence, five-treatment, two-period, single centre study.

Findings from the study demonstrated good linearity and dose-proportionality for betamethasone blood concentrations at 0.0125 (low), 0.5 (medium) or 0.1 (high) mg/kg dose levels of GTX-102.