Research Models

Gba1 L444P KI Mouse (MMRRC)

Synonyms: GbaL444P, GbaL444P/L444P, Gba+/L444P

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Species: Mouse
Genes: Gba1
Modification: Gba1: Knock-In
Disease Relevance: Parkinson's Disease
Strain Name: B6;129S4-Gba1tm1Rlp/Mmnc

Summary

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Dopamine Deficiency
  • α-synuclein Inclusions
  • Motor Impairment
  • Neuronal Loss

No Data

Neuronal Loss

No  deficits in the number of TH-positive neurons in the substantia nigra pars compacta or in the density of TH-immunopositive fibers in the striatum in 8-month-old heterozygous L444P KI mice.

Dopamine Deficiency

Levels  of dopamine, DOPAC (3,4-dihydroxyphenylacetic acid), HVA (homovanillic acid), or their ratio (to assess dopamine turnover) were similar in saline-treated heterozygous KI and wild-type mice at 8 months of age.

α-synuclein Inclusions

α-synuclein levels are increased in the ventral midbrain in heterozygous L444P KI mice at 8 months, as well as in other brain regions assessed at 24 months. Another study, however, reported no differences in total synuclein levels at 3 months, but a decrease in soluble phosphorylated α-synuclein. There is no evidence of α-synuclein aggregates in this model.

Neuroinflammation

GFAP  staining was comparable in heterozygous KI and wild-type mice at 8 and 24 months of age. Iba1 staining, however, was increased in 24-month-old heterozygous KI mice, but only in the granule cell layer of the olfactory bulb.

Mitochondrial Abnormalities

By 8  months of age, heterozygous KI mice have impaired mitochondrial structure (smaller) and function (lower levels of mitochondrial DNA) in the midbrain. Mitochondrial function from cultured cortical neurons also impaired (increased reactive oxygen species generation, decreased mitochondrial complex I enzyme activity, decreased oxygen consumption rate).

Motor Impairment

No differences between heterozygous KI and wild-type mice in open-field test performance at 3 months. At 8 months, heterozygous KI mice also performed at similar levels to wild-type controls on pole and grip strength tests. Heterozygous KI mice may perform better on the pole test at younger (3 months) ages. Pole test performance was also similar between genotypes at 24 months of age.

Non-Motor Impairment

Impaired contextual, but not cued, fear conditioning at 3 months of age in heterozygous KI mice. No deficits in olfaction (buried pellet test) or on the novel object recognition test at 24 months of age.

Last Updated: 30 Jul 2024

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Therapeutics

PMN310

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Overview

Name: PMN310
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: ProMIS Neurosciences, Inc.

Background

PMN310 is a humanized IgG1 monoclonal antibody to soluble Aβ oligomers. It was raised against a constrained cyclic peptide derived from amino acids 13–16 (HHQK) of Aβ. This epitope was predicted by computer modeling to be exposed on toxic Aβ oligomers but not monomers or fibrils. The peptide was reported to accelerate Aβ aggregation in vitro, suggesting this epitope plays a role in seeding the formation of Aβ oligomers, and thus is a good target for inhibition by an antibody (Cashman et al., 2021, AAIC poster).

In preclinical work, PMN310 selectively bound to Aβ oligomers over monomers. It inhibited Aβ oligomer propagation and toxicity in vitro and in cell assays. It prevented Aβ-induced memory deficits, and lessened synaptic loss and inflammation caused by cerebroventricular Aβ-oligomer injection in mice (Kaplan et al., 2023; US Patent 9.216,217 B2).

The antibody did not bind to Aβ plaque or vascular deposits in AD brain tissue sections, but did react with soluble oligomer-enriched fractions (Gibbs et al., 2019). In a direct comparison with other Aβ antibodies, PMN310 was the least affected by high concentrations of competing monomeric Aβ, a characteristic that correlates with clinical efficacy of trialed antibodies (Kaplan et al., 2023 AD/PD poster; Kaplan et al., 2024 preprint). The ability of PMN310 to target oligomers in the presence of competing monomers and plaque suggests a potential for better target engagement in brain and a lower risk of ARIA, compared to other, less-selective antibodies.

Findings

In November 2023, Phase 1 began to evaluate the safety, tolerability, and pharmacokinetics of a single intravenous infusion of PMN310. The placebo-controlled study plans to enroll 40 healthy adult volunteers to five sequential dose cohorts of 175, 350, 700, 1,400, and 2,800 mg. Besides safety endpoints, the study will assess serum and cerebrospinal fluid pharmacokinetics, and anti-drug antibodies. Completion is planned for July 2024.

For details on PMN310 trials, see clinicaltrials.gov.

Last Updated: 19 Jul 2024

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Research Models

Gba1 D409V KI Mouse (Grabowski)

Synonyms: Gba1D409V, 9V, D409V

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Species: Mouse
Genes: Gba1
Modification: Gba1: Knock-In
Disease Relevance: Parkinson's Disease
Strain Name: Gba1tm4Ggb

This knock-in (KI) mouse model was generated by introducing a c.A1366T point mutation into exon 9 of the mouse Gba1 (acid β-glucosidase) gene resulting in a D409V substitution (Xu et al., 2003).

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Neuroinflammation
  • Neuronal Loss

No Data

  • Dopamine Deficiency
  • Mitochondrial Abnormalities

Neuronal Loss

No neurodegeneration in the hippocampus, striatum, or substantia nigra at 12 months of age.

Dopamine Deficiency

No data.

α-synuclein Inclusions

Progressive α-synuclein accumulation starting at 6 months of age in homozygous and heterozygous KI mice as well as in D409V/null mice, and may be present even as early as 4 months of age, in the forebrain and hippocampus.

Neuroinflammation

No neuroinflammation observed at 12 months of age in the hippocampus based on GFAP and Iba-1 immunostaining.

Mitochondrial Abnormalities

No data.

Motor Impairment

Homozygous KI mice do not exhibit gait abnormalities or locomotion based on the open-field test, at 8 and 12 months, respectively. However, D409V/null mice exhibit perturbances in gait as early as 3 months of age.

Non-Motor Impairment

Memory is impaired starting at 4 months in homozygous KI mice based on the novel object recognition and contextual fear-conditioning tests. In D409V/null mice, memory was impaired at 9 months; heterozygous KI mice did not exhibit memory deficits at 6 months. Anxiety- and compulsive-like behaviors were perturbed in D409V/null mice at 6 months, based on the marble burying test.

Last Updated: 16 Jul 2024

COMMENTS / QUESTIONS

  1. Pablo Sardi and colleagues did an excellent job describing the GBA
    mouse model; however, the data/experimental design could not decipher the central
    conundrum, i.e., whether GBA mutations act through a loss of function or a
    toxic gain of function. The authors speculate that glucocerebrosidase replacement may be a
    strategy for the treatment of α-synucleinopathies. This is tautology in the
    paper, but with merit for select patients where GBA mutations can be
    ascribed as a major contributor to disease.

    Sardi et al. did not address the mechanism in the context of past gene discovery, or the new synthesis emerging. Readers may be aware that we recently identified pathogenic mutations in VPS35, a
    central retromer component, in late-onset Parkinson's disease. The paper by
    Vilarino-Guell and colleagues is embargoed in American Journal of Human
    Genetics until 14 July 2011. My reason for mentioning it briefly is that the
    retromer is required to recycle mannose-6-phosphate receptors (MPR) that are
    necessary to traffic lysosomal enzymes, including glucocerebrosidase, from
    the Golgi complex to an acidified (pre)lysosomal compartment.

    Of note, the endosome Rab7L1 (which we postulate explains the PARK16 GWAS signal) is also
    required for proper MPR trafficking and for retromer localization and
    function. Dynactin and tau have also been directly implicated in retromer
    formation and parkinsonism. α-synuclein has been shown to more generally
    disrupt cellular Rab homeostasis, in a dose-dependent manner, and may affect
    multiple trafficking steps between the ER and Golgi. Likewise, LRRK2 GTPase
    and kinase signalling/scaffolding functions are most consistent with its
    complex being a master regulator of membrane protein trafficking.

    Many specific details need to be resolved, but GBA, VPS35, Rab7L1, DCTN1, MAPT, SNCA, and LRRK2—indeed most of the major
    genes identified in late-onset parkinsonism (to date)—now elucidate an
    overlapping biologic network. The phenomenology of selective vulnerability,
    variable expressivity, and penetrance may be addressed using a similar
    framework.

    Ultimately, successful neuroprotective therapeutics for neurodegenerative
    disorders will result from a combination of genetic insight and model
    development, and Pablo Sardi's work nicely illustrates the approach.

    View all comments by Matthew M J Farrer

  2. This PNAS paper represents the latest in a recent flurry of papers (Xu et al., 2010; Cullen et al., 2011; Mazzulli et al., 2011) examining the biochemical and mechanistic links between GBA mutations and synuclein mismetabolism. In the current paper, Sardi et al. find that mice carrying two copies of the D409V mutation in GBA exhibit progressive mismetabolism of synuclein and generalized ubiquitinopathy.

    We made the same observation in these mice in our recent Annals of Neurology paper (Cullen et al., 2011), where we showed an age-dependent increase in the synuclein content of the membrane fraction (containing within it the lysosomal compartment) and ubiquitin staining. Like Sardi et al., we also observed that mice carrying only one copy of the D409V mutation had subtle changes in synuclein levels, supporting the notion of a gain-of-toxic function as at least one aspect of the mechanistic interplay between GBA and synuclein.

    We also showed an accumulation of synuclein in simple cell models when D409V or the similar variant, D409H, was overexpressed. Importantly, when we overexpressed wild-type GBA in cells, we observed a significant reduction in cellular synuclein levels. This was the case in both PC12 cells, which were transfected with GBA, and in HEK293 cells, which experienced a more robust increase in GBA expression and activity due to viral overexpression.

    Sardi et al. have now extended our observations into animals by showing that viral overexpression of wild-type GBA into rodent brain can reduce the synuclein accumulation and memory deficits caused by GBA mutation. Thus, as discussed in our Annals Neurology paper (Cullen et al., 2011), and as demonstrated by Sardi et al., increasing the brain's GBA content may be a viable therapeutic strategy to explore further. Perhaps eventually, a combination approach may be used, with GBA expression utilized to combat loss of enzyme function, and GBA chaperoning and/or lysosomal support (see, e.g., our results with isofagomine and rapamycin) utilized to combat a gain of toxic function of mutant GBA.

    References:

    Xu YH, Sun Y, Ran H, Quinn B, Witte D, Grabowski GA. Accumulation and distribution of α-synuclein and ubiquitin in the CNS of Gaucher disease mouse models. Mol Genet Metab. 2011 Apr;102(4):436-47. Epub 2010 Dec 31 PubMed.

    Cullen V, Sardi SP, Ng J, Xu YH, Sun Y, Tomlinson JJ, Kolodziej P, Kahn I, Saftig P, Woulfe J, Rochet JC, Glicksman MA, Cheng SH, Grabowski GA, Shihabuddin LS, Schlossmacher MG. Acid β-glucosidase mutants linked to Gaucher disease, Parkinson disease, and Lewy body dementia alter α-synuclein processing. Ann Neurol. 2011 Jun;69(6):940-53. Epub 2011 Apr 6 PubMed.

    View all comments by Valerie Cullen

  3. The paper by Sardi et al., 2011, provides further important in-vivo evidence of a mechanistic link between Gaucher’s disease and α-synuclein processing. The demonstration that accumulation of α-synuclein and behavioral deficits in Gaucher's disease mice can be ameliorated by increasing glucocerebrosidase levels suggests that this lysosomal enzyme may be an important therapeutic target for the treatment of synucleinopathies. It will be of future interest to determine whether enhancing glucocerebrosidase function, either through adenoviral-mediated glucocerebrosidase expression or administration of pharmacological chaperones, has the ability to reverse or clear the accumulation of α-synuclein in aged (12-month-old) Gaucher's mice that are symptomatic.

    The recent exciting paper by Lim et al. (Lim et al., 2011), which demonstrates that behavioral deficits and pathology induced by α-synuclein overexpression can be reversed, suggests that methods that enhance the clearance of α-synuclein may provide therapeutic benefit even after symptoms are apparent. Augmentation of glucocerebrosidase function appears to be one such option that may accelerate the clearance of α-synuclein and prevent further disease progression in Parkinson's disease and other synucleinopathies.

    References:

    Lim Y, Kehm VM, Lee EB, Soper JH, Li C, Trojanowski JQ, Lee VM. α-Syn suppression reverses synaptic and memory defects in a mouse model of dementia with Lewy bodies. J Neurosci. 2011 Jul 6;31(27):10076-87. PubMed.

    View all comments by Joseph Mazzulli

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Therapeutics

AVB-101

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Overview

Name: AVB-101
Therapy Type: DNA/RNA-based
Target Type: Other (timeline)
Condition(s): Frontotemporal Dementia
U.S. FDA Status: Frontotemporal Dementia (Phase 1/2)
Company: AviadoBio

Background

AVB-101 is a gene therapy designed to deliver a copy of the human progranulin gene to the brain. It is being tested in people with frontotemporal dementia due to pathogenic progranulin mutations. These patients have abnormally low expression of progranulin in the brain, and the goal of this gene therapy is to restore progranulin concentration and function.

AVB-101 is derived from a non-replicating adeno-associated virus, serotype 9 (AAV-9), modified to contain a copy of the non-mutated human PGRN gene under control of a neuron-specific promoter. Thus, the tropism of the virus and gene construction are designed to restrict expression to neurons. The treatment is given as a one-time infusion into the thalamus, using MRI-guided stereotactic surgery. Thalamic delivery is intended to maximize distribution to multiple areas of the cortex via the brain’s extensive thalamo-cortical neural network.

No preclinical work is published on AVB-101. At conferences, the company has shown data indicating that thalamic delivery in progranulin knockout mice re-established protein expression and reversed phenotypes of lysosome dysfunction and neuroinflammation. The company reported that MRI-guided thalamic infusion in sheep and monkeys produced broad brain expression of human progranulin. Thalamic infusion was claimed to give wider distribution and higher expression at lower viral doses compared to delivery by injection into the CSF of the cisterna magna. In monkeys, progranulin concentrations reached physiological levels in the frontal and temporal lobes that are most affected in FTD. The treatment caused no overt toxicity in the animals. The monkeys developed low-grade microgliosis in the thalamus and midbrain, which was more pronounced at higher doses and increased over six months. No progranulin expression and little viral material was found outside the brain (2022 slides; 2022 poster; 2023 poster).

Findings

In August 2023, AviadoBio began a Phase1/2 trial to assess the safety and ability of AVB-101 to restore progranulin levels in people with frontotemporal dementia with progranulin mutations. The open-label study plans to enroll nine participants in two dose cohorts. Patients with mild or moderate dementia will receive a single, bilateral, MRI-guided thalamic infusion of AVB-101, and be followed up for five years. The primary outcomes are adverse events, change from baseline in MMSE, and time for clearance of virus material from the body, as well as clinical, lab, or MRI abnormalities. Secondary outcomes span progranulin and neurofilament light chain levels in CSF and blood, antibodies to AAV9 and progranulin, and brain volume by MRI, plus cognitive, clinical, and other measures. The trial is running at multiple sites in Europe and the U.S. until October 2030.

AVB-101 has Orphan Drug and Fast Track status from the U.S. FDA.

For details on AVB-101 trials, see clinicaltrials.gov.

Last Updated: 02 Jul 2024

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Therapeutics

Low Dose Interleukin-2

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Overview

Name: Low Dose Interleukin-2
Synonyms: COYA-301, Aldesleukin, Proleukin, COYA-302, ld IL-2
Therapy Type: Other
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease, Amyotrophic Lateral Sclerosis
U.S. FDA Status: Alzheimer's Disease (Phase 2), Amyotrophic Lateral Sclerosis (Phase 3)
Company: Coya Therapeutics

Background

Low-dose interleukin 2 is being tested as an immunomodulatory approach in neurodegenerative diseases. It increases the number and activity of regulatory T cells (Tregs) that suppress inflammation. At high doses, IL-2 stimulates the immune response to tumors, and is approved for treating cancer.

Treg-mediated immune control appears to be compromised in people with AD (Faridar et al., 2020). In preclinical studies, Tregs that were transferred into AD mice entered the brain and stopped Aβ plaque growth (Faridar et al., 2022). Multiple labs have reported that low-dose IL-2 induces expansion of Treg cells, decreases hippocampal Aβ plaque load, and lessens memory deficits in APP/PS1 mice (Dansokho et al., 2016; Alves et al., 2017; Yuan et al., 2023).

Tregs also play a role in ALS and in Parkinson’s disease. In people with ALS, an observed decline in Tregs correlated with faster disease progression. In the SOD1 mouse model of ALS, giving IL-2 or Tregs resulted in motor neuron preservation, less spinal cord inflammation, and longer survival (Sheean et al., 2018; Banerjee et al., 2008). A Phase 1 study in ALS patients demonstrated reduction in markers of oxidative stress and inflammation after Treg infusion (Beers et al., 2022).

In PD patients, reductions in Treg number and function correlated with proinflammatory T cell activation, and increases in Tregs were associated with improved clinical measures (Thome et al., 2021; Arce-Sillas et al., 2024). Administration of low-dose IL-2 led to Treg expansion in a mouse model of PD (Markovic et al., 2022). In other preclinical studies, transplantation or expansion of Tregs was neuroprotective in rodent models of PD (Reynolds et al., 2010; Badr et al., 2022; Park et al., 2023).

Findings

In June 2019, academic investigators in Houston, Texas, began an open-label feasibility study of low-dose commercially available recombinant human IL-2 in people with AD dementia. Eight participants injected 1 million units of Aldesleukin daily for five days per month, for four months. Results are published (Faridar et al., 2023). The treatment was safe and well-tolerated. Most common adverse events were injection site reactions and mild leukopenia, each affecting one-third of patients. After each cycle, participants had increased Treg numbers and function, which returned to baseline between treatments. IL-2 treatment downregulated inflammatory cytokine expression in circulating monocytes, and some plasma pro-inflammatory markers decreased compared to baseline. The investigators claimed an improvement on the MMSE that reverted to baseline after treatment had ended. ADAS-Cog and CDR-SB scores did not change.

In 2020, COYA Therapeutics was founded by the Houston researchers to develop low-dose IL-2 under the name COYA-301. The company presented more results of the open-label AD study in May 2023, indicating a significant lowering of monocyte inflammatory mediators TNFα, IL-6, and IL-1β after treatment. In one patient, TSPO-PET scans suggested a reduction in brain inflammation two weeks after the last dose (slides).

In January 2022, Phase 2 began with support from the Gates Foundation and the Alzheimer’s Association. The Houston investigators enrolled 38 AD patients with mild to moderate dementia, for six months of Aldesleukin, given as a five-day course by subcutaneous injection once or twice per month. The primary endpoint was safety and tolerability. Change in Tregs as a percentage of total CD4 T cells served as a secondary endpoint. In May 2024, COYA announced completion of the study, with results to follow later in the year (press release).

In September 2022, an independent Phase 2 trial began enrolling 45 AD patients with mild dementia at the Centre Hospitalier St. Anne in Paris. Treatment consists of 1 million units of IL-2 or placebo, on a schedule of daily injections for five days, followed weekly injections for four months. The primary endpoint is change in Clinical Dementia Rating 18 months after the first injection. Other endpoints include the MMSE, ADAS-Cog, ADCS-ADL, CDR-SB, change in Tregs and other immune cells, PET scans for neuroinflammation, hippocampal atrophy, and safety. The trial will run until September 2025.

In March 2023, a biomarker study began to assess the effects of low-dose IL-2 on CSF and blood markers of inflammation, and on brain inflammation using the ER176 PET tracer that binds TSPO. This placebo-controlled study will enroll 40 patients in Houston, to receive IL-2 every two or four weeks for six months. The study will run until December 2025.

Testing of low-dose IL-2 for ALS began in 2015, with a Phase 2 trial by researchers in Nimes, France. Thirty-six patients received 1 or 2 million units of IL-2, or placebo, by subcutaneous injection for five days each month for three months, in addition to riluzole. IL-2 was tolerated, with mild adverse events that included injection site reactions and flu-like symptoms. The study achieved its primary outcome of increasing Tregs in the treatment groups. The plasma inflammation marker CCL2 decreased dose-dependently, but there was no change in the surrogate efficacy marker of plasma neurofilament light (Camu et al., 2020). Analysis of leucocyte gene expression showed a dose-dependent increase in Treg markers at the end of treatment (Giovanelli et al., 2021). Inhibition of inflammatory gene expression was apparent after the first cycle of treatment, and was less pronounced after three cycles. Higher baseline inflammatory gene expression predicted poorer response to treatment.

From 2017-2021, researchers followed up with a larger Phase 2 trial in France and the U.K. The MIROCALS study enrolled 220 patients newly diagnosed with ALS, for five-day courses of 2 million units Il-2 per day, or placebo, monthly for 18 months. The primary outcome was survival. Results were announced in December 2022 (press release). Treatment was safe, tolerated, and resulted in elevated Treg numbers. Treatment was associated with a non-significant 19 percent reduction in the risk of death. In a prespecified subgroup analysis, participants with low CSF phosphorylated neurofilament heavy chain and less aggressive disease had a significant 40 percent increase in survival. This subgroup included most of the participants in the trial.

From 2019-2022, investigators in Houston and Boston tested the combination of monthly injections of patient-derived Tregs with low dose IL-2 in 12 ALS patients. The treatment was safe and resulted in elevations of Treg suppressive function (Thonhoff et al., 2022).

In 2020, another open-label trial began recruiting 13 ALS patients in China; its status is unknown.

In October 2021, COYA started an open label study in people with ALS of low-dose IL-2 in combination with CTLA4-IgG. Called Abatacept, this drug suppresses the activation of monocytes and microglia; it is used to treat autoimmune diseases. The company is testing this dual immunomodulator under the name COYA-302. The study, at the Houston Methodist Research Institute, planned to treat 10 patients every two weeks for one year, and assess safety and tolerability. Secondary and exploratory outcomes include Treg function, serum biomarkers of oxidative stress, inflammation, and neurodegeneration, and clinical functioning on the ALSFRS-R scale. Results are published (Thonhoff et al., 2024). Four patients enrolled; all completed it without serious adverse events. Increases in Treg in number and function occurred over the entire treatment period, and returned to baseline levels after treatment stopped. Biomarkers showed trends to reduction in the first 16 weeks, but were not uniformly changed. ALSFRS-R scores remained stable over 48 weeks.

In May 2024, the Houston researchers began a small trial testing COYA-302, dosed every two or four weeks, in 10 frontotemporal dementia patients. The open-label treatment will run for six months with a primary outcome of safety, and a secondary outcome of blood Treg numbers. Completion is expected in April 2026.

For details on low dose IL-2 trials, see clinicaltrials.gov.

Last Updated: 28 Jun 2024

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Research Models

Vps35 p.D620N KI Mouse

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Species: Mouse
Genes: Vps35
Modification: Vps35: Knock-In
Disease Relevance: Parkinson's Disease
Strain Name: B6.Cg-Vps35tm1.1Mjff/J

Modification Details:

Summary

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Non-Motor Impairment

No Data

Neuronal Loss

Loss of TH-positive neurons in the SNpc and loss of TH-positive nerve terminals in the striatum at 13-16 months. Widespread axonal degeneration in the brain at 13 months.

Dopamine Deficiency

Enhanced peak amplitude in dopamine release and prolonged reuptake kinetics in acute striatal slices from 3-month-old mice; decreased DAT and increased VMAT2. Basal levels of dopamine and metabolites in dorsolateral striatum did not differ, but the DOPAC+HVA/DA ratio was increased. At 16 months, dopamine in striatal homogenates was reduced, but levels of metabolites (DOPAC, HVA) did not differ.

α-synuclein Inclusions

No differences in α-synuclein puncta density or distribution in the SNpc at 3 months. No pathological α-synuclein observations seen throughout the brain at 13 months. However, at 15 to 16 months, increased somatic α-synuclein immunoreactivity found in the SNpc, and increased α-synuclein oligomers and aggregated α-synuclein observed in the ventral midbrain.

Neuroinflammation

Increased GFAP immunostaining in the SNpc, but not in the striatum, of 15- to 16-month-old VKI mice; no GFAP differences observed at earlier ages. No differences in microgliosis (Iba-1 immunostaining) in the SNpc or the striatum up to 16 months of age.

Mitochondrial Abnormalities

Mitochondrial structure, assesed by EM, was perturbed at 14 months, but not at 3 months, of age. Mitochondrial function—namely, the oxygen consumption rate—was reduced in older (15-month-old) mice.

Motor Impairment

Motor deficiencies on the open-field test and the beam walking test appear at 14 months of age, but not earlier from 3 to even 13 months of age. However, performance on other motor tests—Rotarod and grip strength—did not differ at the advanced age (14 months). No deficits seen in the cylinder test (rearing) at 3 months. Amphetamine-induced hyperlocomotion is rescued by LRRK2 kinase inhibition.

Non-Motor Impairment

No deficits in the buried pellet test, measuring olfactory function, from 6 to 14 months of age. No defects in gastrointestinal function (as measured by stool frequency and water content) up to 14 months of age.

Last Updated: 17 Jun 2024

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Further Reading

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Research Models

Gba1 D409V KI Mouse (MJFF)

Synonyms: Gba D409V KI   , Gbatm2636(D427V)Arte

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Species: Mouse
Genes: Gba1
Modification: Gba1: Knock-In
Disease Relevance: Parkinson's Disease
Strain Name: C57BL/6N-Gba1tm1.1Mjff/J

Summary

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.

Absent

  • Neuronal Loss

No Data

  • Mitochondrial Abnormalities

Neuronal Loss

No differences in the number of dopaminergic neurons in the substantia nigra pars compacta were found between homozygous KI mice and wild-type mice at 4, 8, and 12 months of age.

Dopamine Deficiency

Dopamine levels did not differ at 4, 8, and 12 months of age, but dopamine turnover (ratio of DOPAC and HVA to dopamine) tended to increase, though the increase was only significant at 12 months of age.

α-synuclein Inclusions

Homozygous KI mice have higher levels of soluble monomeric α-synuclein in the hippocampus at 12 months than heterozygous KI mice and wild-type controls. Levels of pathologic phosphorylated form pS129 do not differ between homozygous KI mice and controls in the substantia nigra, cortex, or hippocampus.

Neuroinflammation

Data are mixed on levels of GFAP and Iba-1 immunostaining in KI mice brain. One study in homozygous KI mice found no differences in the striatum and substantia nigra at 4, 8, or 12 months of age; another found decreased GFAP staining in the substantia nigra at 12 months; and a third study (het mice) found increased GFAP and Iba-1 in the hippocampus at 12 months.

Mitochondrial Abnormalities

No data.

Motor Impairment

Homozygous D409V KI mice generally exhibit motor function similar to wild-type controls (open-field, Rotarod, grip strength, swim velocity). However, a couple of exceptions found in one study were greater grip strength force at 12 months of age and transiently increased locomotor activity on the open-field test at 8 months of age.

Non-Motor Impairment

Cognitive performance was impaired in 12-month-old heterozygous KI mice (but not at 3, 6, or 9 months), based on the Morris water maze and Y-maze. Anxiety-like behavior (based on the open-field test) did not differ at 12 months.

Last Updated: 14 Jun 2024

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Therapeutics

VY-TAU01

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Overview

Name: VY-TAU01
Synonyms: HC3LC2, Voyager_9
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Tau (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Voyager Therapeutics

Background

VY-TAU01 is a recombinant, humanized IgG4 monoclonal antibody to an epitope in the C-terminus of tau. It is designed to block the spread of pathological tau.

According to a poster presented at AAIC 2022, this antibody was generated by immunizing mice with paired helical filamentous tau isolated from human brain. More than 700 monoclonal antibodies were screened for selectivity to pathological tau, as well as for their ability to inhibit seeding of tau aggregates in vitro and spreading of tau pathology in mice. Voyager presented data demonstrating that the most efficacious C-terminal antibody, Ab01, inhibited the spread of pathological tau by greater than 70 percent in the P301S mouse seeding model. This mouse IgG1 antibody was subsequently humanized to generate the clinical candidate (AD/PD 2023 conference poster).

In nonhuman primates, blood levels after intravenous administration were dose-proportional. The antibody’s half-life was 11-12 days, CSF exposure was approximately 0.1-0.2 percent of serum (AD/PD 2024 poster). There was no indication of a significant anti-drug antibody response.

Findings

On May 16, 2024, Voyager announced the start of clinical development with a single-ascending-dose safety and pharmacokinetic study of intravenous VY-TAU01 (press release). The trial expects to enroll 48 healthy volunteers in multiple dose cohorts. The trial was not found in registries.

Last Updated: 03 Jun 2024

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Therapeutics

NX210c

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Overview

Name: NX210c
Synonyms: HWSGWSS[CSRSC]GOH (brackets represent the disulfide bond)
Chemical Name: H-L-tryphophanyl-L-seryl-glycyl-L-tryptophanyl-L-seryl-L-seryl-L-cysteinyl-L-seryl-L-arginyl-L-seryl-L-cysteinyl-glycyl-OH (disulfide bond)
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis, Parkinson's Disease
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Phase 2), Parkinson's Disease (Phase 1)
Company: Axoltis Pharma

Background

NX210c is a cyclized 12-amino-acid peptide derived from a protein involved in embryonic neuronal development. It is delivered by intravenous injection.

This peptide was designed from the most conserved sequence of the thrombospondin repeats from the SCO-spondin protein. SCO-spondin, a large, multifunctional glycoprotein specific to the CNS extracellular matrix, is produced by the subcommissural organ during embryogenesis, and is essential for neural development. SCO-spondin has also been proposed to function in adult neurogenesis (Inada et al., 2023).

Both linear and cyclic forms of this peptide have been evaluated preclinically. The linear NX210 is converted in vivo to NX210c by formation of an intrachain disulfide bridge between two cysteines. In a mouse amyloidosis model, NX210 and NX210c reduced pathologic markers of Aβ42, p-Tau, and inflammation, after intraventricular injection of Aβ oligomers (Le Douce et al., 2021). In this study, conducted by Axoltis researchers, the peptides improved behaviors related to cognition and memory in the Y maze, passive avoidance test, and Morris water maze.

In other Axoltis-sponsored preclinical work, NX210 protected against oxidative stress and stimulated axonal regrowth and functional recovery in a spinal cord injury model (Sakka et al., 2014). NX201 and NX201c both protected neurons from glutamate excitotoxicity by disrupting the apoptotic signaling cascade; NX210c was more effective (Deletage et al., 2021). NX210c increased synaptic transmission in brain slices, and improved memory in mice treated with the NMDAR agonist phencyclidine (Lemarchant et al., 2022). The company also claims that NX210c reduces blood-brain barrier permeability, but that data is not public. In the only published study independent of Axoltis, NX210 protected against cell loss in ischemic stroke models (Yang et al., 2022).

Findings

From June to November 2020, the company conducted a Phase 1 safety trial of NX210. It enrolled 39 healthy adults in five cohorts, to receive single intravenous doses of 0.4, 1.25, 2.5, 5, or 10 mg/kg, or placebo. According to published results, one-third of participants reported mild adverse events. The most common were dizziness, headache, and sleepiness. NX210 cyclized to NX210c in blood. The peptide was widely distributed and rapidly cleared, with a half-life in plasma of 20 minutes or less. Potential pharmacodynamic effects were reported on EEG, and on plasma tryptophan and homocysteine (Bourdes et al., 2022).

In October 2022, the FDA granted NX210c Orphan Drug Designation for ALS.

In December 2022, a multiple-dose Phase 1 trial began enrolling 29 healthy aged volunteers. Thirty participants are to receive 5 or 10 mg/kg NX210c or placebo by 10-minute intravenous infusion three times a week for four weeks. The primary outcome is adverse events; blood and CSF pharmacokinetic measures serve as secondary outcomes. The study assesses neurologic safety using the Neurocart Battery, as well as 34 blood and 16 CSF biomarkers. Conducted in the Netherlands, the trial is set to finish in December 2024.

In December 2023, the company announced initial results (press release). The treatment remained safe and well-tolerated, with mild adverse events and no evidence of neurologic harm. Data presented at the 2024 AD/PD conference in Lisbon claimed decreases in blood homocysteine and the tight junction protein claudin 5, which were interpreted as evidence of blood-brain barrier repair. Blood levels of neurofilament light chain were said to decrease, although no numbers were shown. Changes in blood and CNS biomarkers were sustained for 40 days of follow-up, despite the drug’s short plasma half-life. The company plans to expand this trial to enroll people with Parkinson’s disease.

In April 2024, the company registered a Phase 2 trial  in ALS. To begin in September 2024, it will recruit 80 adult patients. The trial will compare four weeks of thrice-weekly 5 or 10 mg/kg doses to placebo, with a three-month follow-up. The sole outcome listed on clinicaltrials.gov is blood neurofilament light, or the CSF/serum albumin ratio, an indicator of blood-brain barrier integrity. Completion is expected in February 2026.

For details on NX210c trials, see clinicaltrials.gov and the WHO Trial Registry.

Last Updated: 03 Jun 2024

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Therapeutics

Selnoflast

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Overview

Name: Selnoflast
Synonyms: RO7486967, RG-6418, IZD-334, somalix
Chemical Name: 1-ethyl-N-[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]piperidine-4-sulfonamide
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 1)
Company: Hoffmann-La Roche, Inflazome Ltd.

Background

Selnoflast is an inhibitor of inflammasomes containing NLRP3, or nod-like receptor family, pyrin domain-containing protein 3. Inflammasomes are multiprotein, cytosolic complexes that function as sensors in the innate immune system. Their activation by pathologic proteins and other stressors triggers production and secretion of proinflammatory cytokines IL1-β and IL-18, and can induce cell death. NLRP3-containing inflammasome activation occurs in many conditions where chronic inflammation plays a role, including Alzheimer’s and Parkinson’s diseases (reviewed in Heneka et al., 2018). Multiple NLRP3 inhibitors are in clinical trials for a range of inflammatory diseases (Li et al., 2023). According to company information, selnoflast does not enter the brain.

NLRP3 is a receptor for Aβ, and mediates the innate immune response to amyloid in microglia, cells involved in Alzheimer’s pathogenesis (Halle et al., 2008). Deleting NLRP3 in the APP/PS1 mouse model diminishes Aβ deposition, synapse loss, and memory deficits (Heneka et al., 2013). Loss of NLRP3 also prevents tau tangle formation in human tau-expressing mice in response to injected Aβ (Ising et al., 2019).

No preclinical data is published for selnoflast, also known as RO7486967. It is one of a series of compounds related to the NLRP3 inhibitor MCC950, which was shown to block inflammasome activation, promote microglial clearance of Aβ, reduce Aβ accumulation, and improve cognitive function in APP/PS1 mice (Coll et al., 2015; Dempsey et al., 2017). MCC950 also prevented inflammasome activation by fibrillar α-synuclein, and led to less neuron loss and better dopaminergic signaling in Parkinson’s disease models (Gordon et al., 2018). The scientists behind these studies founded Inflazome, which developed and held the patent on MCC950 and related compounds.

Findings

From September 2019 to February 2020, Inflazome conducted Phase 1 single- and multiple-ascending-dose study of selnoflast in 64 healthy adults and patients with cryopyrin-associated periodic syndrome. CAPS is an autoimmune disease caused by gain-of-function mutations in the NLRP3 gene, and affects both peripheral organs and the central nervous system. According to a February 2020 press release, the drug was safe and tolerable, with dose-proportional pharmacokinetics and pharmacodynamic effects.

In October 2020, Roche acquired Inflazome. The company abandoned a planned study of another NLRP3 inhibitor inzomelid/emlenoflast, and began developing selnoflast.

Starting in November 2021, Roche sponsored a Phase 1b study in 19 patients with ulcerative colitis, treated with 450 mg or placebo, once daily for seven days. Serum drug concentrations were claimed to exceed those required for 90 percent NLRP3 inhibition throughout the dosing period. Target engagement was confirmed by the diminished production of IL-1β by blood cells following ex-vivo LPS stimulation. Treatment did not change plasma IL-18, nor did it alter IL-1-related gene expression in colon tissue biopsies. Selnoflast-treated participants had more adverse events than those on placebo. None were serious; headache and indigestion were most common. The investigators concluded the drug was safe and well-tolerated, but unlikely to affect inflammation in patients with ulcerative colitis (Klughammer et al., 2023).

In September 2022, the company began a Phase 1b trial in 72 people with early Parkinson’s disease. The study, at 20 centers in Europe and the U.S., compares 28 days of RO7486967 to placebo against primary outcomes of adverse events and suicidality. Secondary outcomes are pharmacokinetics, and brain neuroinflammation measured by binding of the 18 kDa translocator protein (TSPO) PET ligand [18F]-DPA-714. The trial is expected to finish in January 2025.

Roche is running additional Phase 1b trials for asthma and coronary artery disease. A trial for chronic obstructive pulmonary disease finished in June 2022.

For details of these trials, search for selnoflast, RO7486967, or IZD-334 on clinicaltrials.gov and the International Clinical Trials Registry.

Last Updated: 21 May 2024

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