Species: Mouse
Genes: RAB5A
Modification: RAB5A: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
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+.
Synaptic Loss
Loss of spines in CA3 and dentate gyrus regions of the hippocampus, observed in 8.5-month-old mice.
Neuronal Loss
Loss of basal forebrain cholinergic neurons, beginning at 7 months.
Changes in LTP/LTD
Pronounced defect in LTD and slight impairment in LTD at Schaffer collateral-CA1 synapses in hippocampal slices from 6-month-old mice.
Cognitive Impairment
When tested at 6 months of age, the performance of PA-Rab5 mice differed from wild-type controls in a novel object recognition test.
Last Updated: 31 Jan 2025
Further Reading
No Available Further Reading
Species: Mouse
Genes: Plcg2
Modification: Plcg2: Knock-In
Disease Relevance: Alzheimer's Disease, Dementia with Lewy Bodies, Frontotemporal Dementia
Strain Name: Plcg2em1Bwef
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+.
Gliosis
Astrogliosis revealed by GFAP immunohistochemistry in 6-month-old males. Microglial activation revealed by TSPO PET imaging in year-old females.
Complementary Models
Microglial-like cells derived from human induced pluripotent stem cell lines (hIPSCs) have been used to study PLCγ2 biology in human cells in vitro and in vivo after transplantation into mouse brains.
CRISPR/Cas9 gene editing was used to introduce the PLCG2 P522R mutation into hIPSCs derived from skin cells of an apparently healthy, middle-aged Caucasian male. Isogenic clones homozygous for the wild-type P522 allele or mutant R522 allele were differentiated into microglia-like cells (Maguire et al., 2021). Stimulation of PLCγ2 by Fc receptor ligation led to a greater increase in intracellular Ca2+ in cells carrying the mutant allele, consistent with a hypermorphic effect of the mutation. Similar to microglia and macrophages isolated from Plcg2*P522R knock-in mice (Maguire et al., 2021), hIPSC-derived microglia carrying the mutant allele showed decreased phagocytosis (uptake of E. coli particles or zymosan) and increased endocytosis (uptake of Aβ42 oligomers or Dextrans), compared with isogenic hIPSC-derived microglia expressing wild-type PLCγ2.
A second study compared isogenic hIPSC-derived microglia that differed with regard to P522R gene dose—wild-type (PLCγ2WT), heterozygous for the P522R mutation (PLCγ2HET), and homozygous for the mutation (PLCγ2HOM) (Solomon et al., 2022). In this case, the parental hIPSC line was derived from skin fibroblasts donated by a teenaged male (APOE3/4) of black or African-American ancestry with no diagnosed diseases. Here, too, CRISPR gene editing was used to introduce the PLCG2 P522R mutation. IPSC-derived microglia contained similar levels of PLCγ2 protein, regardless of PLCG2 genotype. However, the genotypes differed with regard to functional properties and gene expression—with PLCγ2HET showing more pronounced differences than PLCγ2HOM on several measures (compared with PLCγ2WT). PLCγ2HOM and PLCγ2HET showed increased uptake of fluorescently labeled Aβ42, but only PLCγ2HET cells showed increased uptake of Dextrans. Uptake of synaptosomes was reduced in P522R carriers, regardless of gene dose. LysoTracker staining—a marker for lysosomes—was elevated in P522R carriers, slightly more so in heterozygotes than homozygotes. When co-cultured with IPSC-derived neurons (heterozygous for the PLCG2 P522R mutation), PLCγ2HET microglia engaged in less synaptic pruning—as measured by PSD95 engulfment—than PLCγ2WT microglia, while PLCγ2HOM did not significantly differ from PLCγ2WT. When levels of expression of selected genes related to microglial function were compared between P522R carriers and wild-type cells, several genes were found to be upregulated in PLCγ2HET—in pathways related to lipid metabolism, lysosomal biogenesis, and immune function—while only APOE was upregulated in PLCγ2HOM. Microglial motility and intracellular Ca2+ levels were also greater in PLCγ2HET compared with the other two PLCG2 genotypes. Physiological studies showed a gene-dose-dependent increase in oxidative phosphorylation with PLCγ2HOM > PLCγ2HET > PLCγ2WT.
A third study focused on the effects of the P522R mutation on the transcriptomes of human microglia-like cells in vivo, in the context of amyloidosis (Claes et al., 2022). Once again, CRISPR gene editing was used to introduce the P522R mutation into the PLCG2 gene, this time in an (RFP)-α-tubulin expressing hIPSC line derived from fibroblasts donated by an apparently healthy 30-year-old Japanese man. IPSCs homozygous for the PLCG2 P522R mutation or isogenic hIPSCs with wild-type PLCG2 were differentiated into microglia-like cells in vitro, then grafted into the brains of neonatal immune-deficient 5xFAD or non-transgenic mice. Mice were aged to 7 months, a time when plaque deposition is well underway in 5xFAD brains, and the human cells were harvested for RNA sequencing. PLCG2 P522R microglia from 5xFAD brains showed increased levels of expression of multiple HLA and interferon genes and of genes encoding chemokines that mediate T-cell recruitment to the brain, compared with microglia expressing wild-type PLCG2. Gene Ontology analysis highlighted MHC class II antigen presentation, cytokine/chemokine signaling, interferon signaling, and regulation of T cell proliferation as pathways affected by the P522R mutation. PLCG2 P522R microglia isolated from non-transgenic hosts also showed increased expression of HLA genes, compared with microglia carrying wild-type PLCG2.
Chimeric 5xFAD brains were also examined histologically, and no differences were seen between those transplanted with P522R and wild-type PLCG2 hIPSC-derived microglia in the following measures: amyloid plaque burden, number, or size; microglial morphology, number of plaque-associated microglia, or microglial amyloid internalization; “amount” of plaque-associated dystrophic neurites; or numbers of total or plaque-associated astrocytes.
The lack of an effect of the P522R mutation on amyloid-related pathology in chimeric mice contrasted with findings in 5xFAD mice in which the P522R mutation was knocked into the endogenous Plcg2 gene. In the knock-in mice, the P522R mutation reduced amyloidosis, enhanced microglia-plaque interactions, and protected against plaque-associated pathology. The chimeric and knock-in models differ in several aspects that could potentially contribute to these discrepant findings, including intrinsic differences between human and mouse microglia, expression of P522R PLCγ2 in cells other than microglia in the knock-in mice, and lack of immune responses in chimeric hosts.
Last Updated: 27 Oct 2023
Further Reading
No Available Further Reading
Species: Mouse
Genes: Atg16l1
Modification: Atg16l1: Knock-Out
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
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+.
Plaques
Intracellular and extracellular Aβ deposits, but no dense-core plaques, in 2-year-old mice.
Neuronal Loss
Apparent neuron loss in hippocampi of 2-year-old mice (fewer neurons, increased levels of cleaved caspase-3, and increased numbers of TUNEL-positive neurons).
Gliosis
Microgliosis in the hippocampi of 2-year-old mice.
Changes in LTP/LTD
Impaired long-term potentiation at CA3-CA1 synapses.
Cognitive Impairment
Deficits in the sucrose preference test, spontaneous alternation in the Y-maze, and novel object recognition test.
Last Updated: 12 Nov 2020
Further Reading
No Available Further Reading
Overview
Name: Losartan
Synonyms: Cozaar®, MK0954
Chemical Name: 2-butyl-5-chloro-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Merck
Approved for: Hypertension, diabetic neuropathy
Background
Losartan is an angiotensin II receptor blocker used to treat high blood pressure. It reduces the risk of stroke in people with hypertension and an enlarged heart. It is also used to protect against kidney damage due to diabetes. Approved in 1995, losartan is available in branded and generic forms. In 2017, it was the ninth-most-prescribed medication in the U.S. Common side effects include muscle cramps, stuffy nose, dizziness, and back pain. Losartan crosses the blood-brain barrier.
Managing hypertension with medications reduces the risk of mild cognitive impairment (Jan 2019 news). Losartan other angiotensin receptor blockers (ARBs) act on the renin-angiotensin system, which regulates blood pressure in the body and the brain. Angiotensin II receptors also mediate inflammation, blood-brain barrier maintenance, and neuron survival. Genetic, epidemiologic, and biological evidence implicates changes in the brain renin-angiotensin system in Alzheimer’s disease (reviewed in Kehoe, 2018).
ARB use is associated with a reduced incidence of cognitive impairment, dementia, and AD, which may be independent of lowered blood pressure (e.g., Wharton et al., 2015; Barthold et al., 2018; also see Walker et al., 2020). ). However, meta-analyses do not support a benefit of ARBs over other classes of antihypertensives in preventing cognitive decline or dementia (Peters et al., 2020; Ding et al., 2020). In people with mild cognitive impairment, use of ARBs, but not other antihypertensives, was linked to lower brain amyloid load and CSF tau (Hajjar et al., 2012; Hajjar et al., 2015).
In animal models of AD, losartan given systemically attenuates brain inflammation and cognitive impairment, without affecting soluble Aβ or plaque load (e.g., Ongali et al., 2014). In other studies, intranasal or intraperitoneal losartan reduced Aβ plaques and inflammatory markers and stimulated neurogenesis in APP/PS1 mice, but no behavioral data were reported (Danielyan et al., 2010; Drews et al., 2021). In mice expressing a variant of the angiotensin-converting enzyme that raises the risk of AD in people, losartan prevented neurodegeneration (Oct 2020 news).
In other preclinical work, losartan reversed scopolamine-induced memory deficits in mice (Ababei et al., 2019), and reduced inflammation, perivascular Aβ deposits, and neurological deficits in hypertensive rats (Drews et al., 2019). Losartan also reportedly inhibits platelet-mediated Aβ aggregation, a possible contributor to cerebral amyloidosis (Donner et al., 2020).
Some animal studies suggest that losartan’s cognitive benefits depend on activation of the angiotensin IV receptor, which occurs downstream of angiotensin II receptor inhibition (Royea et al., 2017; Royea et al., 2020). In Drosophila, losartan mitigated the toxicity of Aβ or a presenilin mutation independently of the renin-angiotensin pathway (Lee et al., 2021).
Findings
In 2013, the Phase 2 RADAR trial began testing the effects of one year of losartan treatment on brain structure in people clinically diagnosed with mild to moderate Alzheimer’s disease (Kehoe et al., 2018). All 261 participants started with a two-week, open-label dose titration to 100 mg losartan daily, the highest dose used for hypertension. The 211 who tolerated treatment went through a wash-out period and were then randomized to drug or placebo. The primary outcome was change in whole-brain volume on MRI; secondary outcomes included the number of white-matter hyperintensities and cerebral blood flow, tests of memory, cognitive function, activities of daily living and quality of life, along with safety and blood pressure monitoring. The study, carried out at multiple sites in the U.K., was completed in May 2019. Losartan did not reduce the rate of brain atrophy or change any secondary measures (Kehoe et al., 2021).
In February 2017, the Phase 2/3 Risk Reduction for Alzheimer’s Disease (rrAD) trial started to evaluate the effect of blood pressure control plus cholesterol lowering, with or without exercise, on cognitive health in people at risk for AD (Szabo-Reed et al., 2019). The trial is enrolling 513 participants without dementia but at high risk for AD due to a family history, or having self-reported subjective cognitive decline. They must be sedentary, and have high blood pressure, treated or untreated. The four-arm design is comparing a regimen of supervised aerobic exercise versus stretching only, with or without losartan and a calcium channel blocker to lower blood pressure, plus atorvastatin. The trial will run for two years, with a primary endpoint of change in neurocognitive function on a composite of the ADCS-PACC and NIH Toolbox Cognition Battery. Secondary outcomes include domain-specific cognitive functions, whole-brain and hippocampal volume on MRI, brain-blood flow, white-matter integrity, and functional connectivity. The trial will run through November 2021 at four sites in the U.S.
In April 2018, a Phase 2 trial began to measure the relationship between hypertension, intracranial blood flow, and Aβ accumulation in older adults. The study is comparing the effects of standard blood pressure control using losartan and amlodipine to reduce systolic blood pressure to less than 130 mmHg, or intensive reduction to less than 120 mm Hg, for one year in 120 older participants with normal cognition. Primary outcomes will be changes in the variability of brain blood flow with each heartbeat, or intracranial pulsatility. Secondary outcomes include CSF Aβ and tau, brain perfusion, structural and functional MRI, measures of neurocognitive function, and patient-reported outcomes of physical and mental health. The trial is slated to end in October 2022.
Two small studies, one completed and one ongoing, are examining the effect of a single dose of losartan on emotional information processing and cognitive function, for the possible treatment of anxiety (Pulcu et al., 2019).
For details on losartan trials in AD, see clinicaltrials.gov.
Last Updated: 04 Nov 2021
Further Reading
No Available Further Reading
Overview
Name: Candesartan
Synonyms: Atacand, Candesartan cilexetil
Chemical Name: 2-ethoxy-1-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1H-1,3-benzodiazole-7-carboxylic acid
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Mild Cognitive Impairment, Alzheimer's Disease
U.S. FDA Status: Mild Cognitive Impairment (Phase 2), Alzheimer's Disease (Phase 2)
Company: AstraZeneca, Takeda Pharmaceutical Company
Approved for: Hypertension, congestive heart failure
Background
Candesartan is an angiotensin II receptor antagonist used around the world to treat elevated blood pressure and congestive heart failure. Approved in 1997, the drug is available in generic form. The most common side effects are dizziness and headache. Candesartan crosses the blood-brain barrier.
Managing hypertension with medications reduces the risk of mild cognitive impairment (Jan 2019 news). Candesartan and other angiotensin receptor blockers (ARBs) act on the renin-angiotensin system, which regulates blood pressure in the body and brain. Angiotensin II receptors also mediate inflammation, blood-brain barrier maintenance, and neuron survival. Genetic, epidemiologic, and biological evidence implicates changes in the brain renin-angiotensin system in Alzheimer’s disease (reviewed in Kehoe 2018). ARB use is associated with a reduced incidence of cognitive impairment, dementia, and AD (e.g., Wharton et al., 2015; Barthold et al., 2018; also see Walker et al., 2020). In people with mild cognitive impairment, use of ARBs, but not other antihypertensives, is linked to lower brain amyloid load and CSF tau (Hajjar et al., 2012; Hajjar et al., 2015). In another study, use of ARBs was associated with slower amyloid accumulation in cognitively normal, amyloid positive people, but not in those with mild cognitive impairment or dementia (Ouk et al., 2021).
Preclinical work in models of chronic hypertension, stroke, kidney disease, and postoperative cognitive dysfunction support the idea that candesartan acts in the brain to attenuate brain inflammation and cognitive impairment, independent of its effect on blood pressure (Ahmed et al., 2018; Ahmed et al., 2018; Li et al., 2014).
In one AD mouse model, the ARB losartan improved memory and reduced plaque load (Wang et al., 2007), though in a similar model, candesartan reduced neuroinflammation but failed to reduce amyloid plaque or improve cognitive function (Trigiani et al., 2018). In 5XFAD mice, intranasal candesartan reduced brain inflammation and reduced amyloid burden by increasing Aβ uptake into microglia; this study did not assess cognition (Torika et al., 2018). A study of mice expressing human APOE4, with or without high Aβ, found candesartan improved memory and hippocampal inflammation in females, but not males (Scheinman et al., 2021).
Findings
Several large studies have evaluated candesartan and cognitive decline in older adults. In the SCOPE trial of nearly 5,000 elderly people with mild hypertension, candesartan reduced nonfatal stroke by one-third compared to other hypertension treatment regimens, but did not change the trajectory of cognitive decline measured by change in the MMSE (Lithell et al., 2003). More extensive cognitive testing in a subset of 257 patients found a small slowing of decline on tests of attention and memory, but no difference in working memory or executive function (Saxby et al., 2008).
In the HOPE3 study of 2,361 older adults with marginally elevated blood pressure, no difference was detected in the rate of decline on tests of executive function or the Montreal Cognitive Assessment in people taking candesartan or placebo for six years (Mar 2019 news; Bosch et al., 2019).
The first trial to evaluate candesartan in people selected for mild cognitive impairment began in January 2008. The Phase 2 AVEC trial compared candesartan to the ACE inhibitor lisinopril or the diuretic hydrochlorothiazide on outcomes of cognition and blood flow in 53 older people with hypertension and cognitive impairment, but without dementia (Hajjar et al., 2009). Candesartan was titrated to a maximum of 32 mg daily, for one year, and all groups received additional anti-hypertensives as needed to achieve a target blood pressure of 140/90. The primary outcomes were tests of executive function and memory, cerebral blood flow, and vasoreactivity. The trial ran at one senior care facility in Massachusetts. According to published results, treatment with candesartan, but not lisinopril or hydrochlorothiazide, led to improved cerebral blood flow and performance on the Trail Making Test Part B measure of executive function (Hajjar et al., 2013).
From August 2014 to December 2018, the same investigators ran a Phase 2 trial comparing candesartan to lisinopril in people over 55 with high blood pressure and executive mild cognitive impairment. Named CALIBREX, this study enrolled 176 participants who received a maximum dose of 32 mg candesartan daily, with other medications as needed to achieve the target blood pressure. The primary outcome was change in executive function measured with the Trail Making Test Part B and the EXAMINER battery. Secondary measures included tests of episodic memory, language, and attention, MRI measures of white-matter hyperintensity, resting-state functional MRI, and ASL-MRI to measure cerebral perfusion. In groups with equally effective blood-pressure control, the candesartan-treated patients did better on the Trail Making Test Part B and HVLT, but not the EXAMINER battery, compared to those on lisinopril (Hajjar et al., 2020).
In June 2016, the Phase 2 CEDAR trial began to test candesartan’s effects in people with Alzheimer’s disease who do not have high blood pressure. The trial enrolled 77 participants with mild cognitive impairment and PET or CSF evidence of brain amyloid, for a one-year, placebo-controlled treatment. Participants received the highest tolerated dose that maintained blood pressure above 100/40 and did not produce symptoms of hypotension, to a maximum of 32 mg daily. The primary outcomes measured tolerability, including symptoms of hypotension, changes in serum creatine or potassium, and the number of people who discontinue drug. Secondary outcomes include changes in CSF pTau181, Aβ42, and cytokines, plus measures of arterial and aortic stiffness. Other outcomes are clinical dementia rating, and tests of executive function and memory, MRI, and functional MRI. In January 2020, amyloid and tau PET were added. The study finished in August 2020; results are published (Hajjar et al., 2022). Candesartan was safe, causing no significant increase in symptoms of hypotension, renal failure, or low serum potassium compared to placebo. Treatment was associated with an increase in CSF Aβ40 and Aβ42. Candesartan did not change brain-wide amyloid PET signals, but did reduce accumulation in the parahippocampal region, and led to an increase in subcortical network functional connectivity. Cognitive tests revealed a transient improvement at six months in the Trail Making Part B test of executive function, and a trend toward improvement in a composite cognitive score. Candesartan did not change CSF tau, hippocampal volume, memory measures, or the CDR-SB.
In both the CALIBREX and CEDAR trials, candesartan treatment led to improved cerebral microvascular function. This was measured by cerebrovascular reactivity to carbon dioxide using blood-oxygenation-level-dependent (BOLD) imaging. In both studies, candesartan treatment was associated with improved whole-brain cerebrovascular reactivity, independent of changes in blood pressure (Henley et al., 2023).
For more details, see clinicaltrials.gov.
Last Updated: 07 Nov 2023
Further Reading
No Available Further Reading
Overview
Name: YTX-7739
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 1)
Company: Yumanity Therapeutics
Background
This is a stearoyl-CoA desaturase inhibitor. SCD catalyzes the rate-limiting step in the production of monounsaturated fatty acids including oleic and palmitoleic acids from saturated fatty acid precursors. The drug is given orally, and was designed to cross the blood-brain barrier.
Oleic acid and SCD activity were found to promote α-synuclein neurotoxicity, and inhibitors of the enzyme to prevent it (Fanning et al., 2019; Imberdis et al., 2019; Vincent et al., 2018). In a mouse model of Parkinson’s disease, an SCD inhibitor calmed resting tremor and slowed progressive motor decline. Treated mice had less toxic insoluble α-synuclein in their brains, and smaller α-synuclein aggregates in dopaminergic nerve fibers than control mice (Oct 2020 news).
Several companies have identified SCD inhibitors for potential treatment of obesity, diabetes, and metabolic disorders, cancer, and acne (Uto 2016). Adverse events in early phase development included hair loss and dry eye.
Yumanity presented preclinical data at the 2021 AD/PD Conference (press release). Four months of oral YTX-7739 dosing in an α-synuclein mouse model reportedly inhibited SCD in brain, improved synuclein pathology, enhanced survival of dopaminergic neurons, and improved motor function. Published data indicate that seven days of dosing produced maximal inhibition of SCD in the brains of rats or monkeys (Tardiff et al., 2022).
Findings
At the 2021 CTAD conference, Yumanity reported results of a Phase 1, single- and multiple-ascending-dose study of YTX-7739 in healthy volunteers. Beginning in October 2019, the single-dose study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamic measures, and the effect of food in 72 men and women who received 5, 10, 30, 100, 250, or 400 mg YTX-7739, given by mouth. The company reported no serious or unexpected adverse events. The most frequent adverse event was headache. Pharmacokinetics were dose-proportional from 5 to 250 mg when the drug was given with food. The multiple-dose study tested 15 or 25 mg once daily for up to 28 days in two cohorts of eight volunteers each. Plasma and CSF pharmacokinetics were dose-proportional with food, and the drug was well tolerated. Target engagement was confirmed by dose-dependent decreases in blood fatty acid desaturation, a biomarker of SCD inhibition. The company is planning a multiple-dosing safety study in healthy volunteers, and a Phase 1b safety and biomarker study in people with Parkinson’s disease.
In November 2021, the company announced top-line results of a Phase 1b study in people with Parkinson’s disease (press release). The data included 20 patients with mild to moderate PD, who received 20 mg drug or placebo for 28 days. The company reported no serious safety events. Treatment with drug was associated with more procedural pain, muscle aches, dry eye, hyperbilirubinemia, pain sensitivity, lower back pain, and constipation than placebo. Target engagement was confirmed by a reduction in fatty acid desaturation in blood and CSF. The company also claimed the drug caused a significant change in quantitative EEG signals in a substudy of eight patients.
On January 19, 2022, Yumanity announced that the FDA had placed a partial hold on multidose trials of YTX-7739 (press release). The hold came in response to the company’s Investigational New Drug application submitted in December 2021, and suspends the initiation of multidose trials in the U.S. A planned single-dose trial will proceed, the company said. No further details were given.
As of January 2022, no clinical trials of YTX-7739 were registered in the U.S. For details, see The Netherlands trial registry.
Last Updated: 26 Jan 2022
Further Reading
No Available Further Reading
Species: Rat
Genes: App, Psen1
Modification: App: Knock-In; Psen1: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Summary
Apphu/hu;Psen1M139T+/+ rats carry a humanized Aβ sequence within the rat App gene and the AD-linked M139T mutation in the rat Psen1 gene. These knock-in animals are homozygous for both humanized App and Psen1 M139T.
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+.
Plaques
No plaques observed up to 2 years of age.
Tangles
No tangles observed up to 2 years of age.
Last Updated: 22 Oct 2020
Further Reading
No Available Further Reading
Species: Rat
Genes: App
Modification: App: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Summary
Apphu/hu rats carry a humanized Aβ sequence within the rat App gene. In this knock-in model, created using CRISPR/Cas9 technology, expression of App is driven by its natural promoter and is expected to show normal cell-type and temporal specificity. Levels of APP are similar in the brains of Apphu/hu and wild-type rats, but the knock-in rats contain more CTFβ, consistent with more efficient BACE1 processing of human APP than rodent APP.
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+.
Plaques
No plaques observed up to 2 years of age.
Tangles
No tangles observed up to 2 years of age.
Last Updated: 22 Oct 2020
Further Reading
No Available Further Reading
Species: Mouse
Genes: App
Modification: App: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: Appem1Bdes
Summary
Apphu/hu mice carry a humanized Aβ sequence within the murine App gene. In this knock-in model, created using CRISPR/Cas9 technology, expression of App is driven by its natural promoter and is expected to show normal cell-type and temporal specificity. Levels of APP are similar in the brains of Apphu/hu and wild-type mice, but the knock-in mice contain more CTFβ, consistent with more efficient BACE1 processing of human APP than rodent APP.
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+.
Last Updated: 22 Oct 2020
Further Reading
No Available Further Reading
Overview
Name: ACI-7104.056
Synonyms: ACI-7104, Affitope PD01A, PD03A
Therapy Type: Immunotherapy (active) (timeline)
Target Type: alpha-synuclein
Condition(s): Parkinson's Disease, Multiple System Atrophy
U.S. FDA Status: Parkinson's Disease (Phase 2), Multiple System Atrophy (Phase 1)
Company: AC Immune SA, AFFiRiS AG
Background
PD01A is an active vaccine to α-synuclein. The immunogen is an eight amino acid peptide that mimics an epitope in the C-terminal region of human α-synuclein, but with a different amino acid sequence. The peptide is conjugated to the carrier protein keyhole limpet hemocyanin and adsorbed to aluminum hydroxide adjuvant. The vaccine is designed to stimulate B cell antibody responses, but bypass auto-reactive T cell mobilization, which can elicit harmful neuroinflammatory responses.
Antibodies to α-synuclein have been shown to prevent pathogenic protein spread and promote clearance of aggregates in animal models (Bae et al., 2012; Masliah et al., 2011). AFFiRiS was developing PD01A and a related vaccine, PD03A, for the synucleinopathies Parkinson’s disease and multiple system atrophy (MSA).
The PD01A immunogen was selected by screening a library of synthetic peptides with a monoclonal antibody to α-synuclein oligomers. When used to vaccinate mice, the PD01A peptide induced antibodies that recognized α-synuclein aggregates preferentially over monomers, and did not react with β-synuclein (Mandler et al., 2014). Immunization of two mouse lines overexpressing human α-synuclein lowered brain levels of aggregated α-synuclein, reduced neurodegeneration, and improved memory and motor behaviors. Immunization likewise decreased neurodegeneration and demyelination in a mouse model of MSA (Mandler et al., 2015). In an APP/α-synuclein double-transgenic mouse, dual immunization with PD01A and an Aβ vaccine had additive benefits on pathology and behavior (Mandler et al., 2019).
Findings
In February 2012, AFFiRiS began a Phase 1 safety and tolerability study of PD01A. The single-site trial in Vienna enrolled 32 people between 45 and 65 years old with early stage idiopathic Parkinson’s disease on stable medication. Twenty-four participants received four doses of 15 or 75 μg PD01A spaced four weeks apart and were observed for one year; eight people served as an untreated comparison group. The company reported favorable findings on safety and immunogenicity (Mar 2015 conference news), and the study was extended to include an additional nine months follow-up. In a second extension, the 22 remaining participants were rerandomized to a single booster of 15 or 75 μg, with 24 weeks follow-up. In a final extension, the 21 remaining participants received a second booster of 75 μg, and were followed for one year. The primary endpoints throughout were adverse events and trial withdrawal. Secondary endpoints included antibody titers, measures of motor and nonmotor symptoms, and CSF levels of α-synuclein, Aβ, and tau.
The trial finished in 2017, and results are published (Volc et al., 2020). The vaccine was well-tolerated, with 21 of 24 participants completing the 3.5-year study. The most common adverse event was transient, local-injection-site reaction. A few percent of participants reported fatigue, headache, and nausea. No one withdrew due to adverse events. MRI revealed no evidence of brain inflammation. Both priming doses produced significant IgG titers in 23 of 24 participants. Antibody levels returned to baseline two years after the first dose, and rapidly increased to higher than the original titers after booster immunizations. Antibodies preferentially bound to α-synuclein oligomers over native α-synuclein, and could be detected in CSF of high responders. A post hoc analysis found a 51 percent reduction in CSF α-synuclein oligomers after four 75 μg priming doses. Total α-synuclein, Aβ, total tau, and phosphoTau181 did not change.
From November 2014 to November 2016, AFFiRiS conducted a Phase 1 study with its second candidate, PD03A, in 36 people with Parkinson’s disease. Participants received four priming vaccinations with 15 μg, 75 μg, or aluminum oxyhydroxide adjuvant four weeks apart, plus a booster at nine months. According to presentation at the AAT-AD/PD Focus Meeting 2018, the vaccine was safe and well-tolerated, and produced a dose-dependent IgG response to α-synuclein (Apr 2018 conference news). Full trial results have been published, reporting that PD03A achieved lower antibody titers than previously observed with PD01A (Poewe et al., 2021).
Beginning in April 2017, the company tested both PD01A and PD03A in 30 people with MSA. The Phase 1 study, at two sites in France, enrolled patients from 30 to 75 years old, in the early stage of disease. Thirty received four subcutaneous injections of 75 μg PD01A or PD03A, once every four weeks, and one booster at nine months; six received the same schedule of adjuvant only. Primary outcome was number of withdrawals and adverse events, plus clinical lab and MRI safety assessments. Secondary measures included antibody titers and change in motor and non-motor symptoms one year after the first vaccination. According to published trial results, the safety profile matched that seen in previous trials for Parkinson’s disease, with injection-site reactions being the most common adverse event (Meissner et al., 2020). Three deaths in the trial were deemed unrelated to immunization. PD01A vaccination generated α-synuclein-reactive IgG in 89 percent of treated patients. The PD03A responder rate was 58 percent, and titers were lower than PD01A.
An additional Phase 1 study was registered in 2016 to be run in Tübingen, Germany, but withdrawn before enrollment began. The study was to have evaluated PD01A versus placebo in 30 PD patients with GBA mutations.
In January 2020, AFFiRiS announced it intended to begin a Phase 2 of PD01A for Parkinson’s disease in late 2020 (press release); no trial was registered.
In July 2021, AC Immune announced it had acquired rights to the PD01 (press release).
In July 2023, a Phase 2 trial began testing an optimized formulation of the vaccine, called ACI-7104.056. The trial's adaptive design will begin enrolling up to three cohorts of 16 early-stage Parkinson’s disease patients, to be randomized 3:1 to vaccine or placebo for 74 weeks. One of the cohorts may be expanded to up to 150 subjects overall, with a randomization of 2:1 active treatment:placebo. Primary outcomes include adverse events, changes on MRI, and levels of α-synuclein antibodies. Secondary outcomes are changes in α-synuclein related biomarkers, dopamine transporter PET scans, and motor and non-motor symptoms. The trial, in Germany, Spain, and the United Kingdom, is expected to finish in January 2028.
In a January 2024 business update, the company reported that enrollment in the first cohort was complete, and the second cohort had started (press release). No safety concerns had emerged.
For details on PD01A and PD03A trials, see clinicaltrials.gov.
For ACI-7104.056, see clinicaltrials.gov.
Last Updated: 05 Feb 2024
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COMMENTS / QUESTIONS
National Institutes of Health
This work points to the central role of early endocytosis in neurodegeneration. Studies of convergence of both GWAS hits and functional studies on early endocytosis, including this one, make it clear that disrupted early endocytosis is a key feature of neurodegeneration. Early endocytic defects have functional consequences beyond just their impact on APP or APP cleavage products.
This study reminds me of work reporting that APOE4 homozygous iPSC-derived neurons also have enlarged early endosomes (Lin et al., 2018), like those observed upon increasing Rab5 expression. Perhaps APOE4 here is having a similar phenotypic effect as increased Rab5 expression.
Interestingly, Lin et al. and our work (Narayan et al., 2020) has shown that, in the context of astrocytes, APOE4 results in a lower number of Rab5+ early endosomes. Overexpression of early endocytic factors like PICALM increases the efficiency of early endocytosis but, surprisingly, leads to compromised early endocytosis in a healthy APOE3 homozygous background. These and other studies make me very curious (1) whether different cell types respond the same way to increased Rab5 expression, and (2) whether increased expression of other early endocytic factors (in otherwise healthy contexts) may lead to similar detrimental consequences?
It is very possible that increasing Rab5 expression, as the authors did in this study, phenocopies the action of other risk factors aside from APOE4. This could suggest a further convergence of risk phenotypes for AD. There is clearly lots to look at in the future!
References:
Lin YT, Seo J, Gao F, Feldman HM, Wen HL, Penney J, Cam HP, Gjoneska E, Raja WK, Cheng J, Rueda R, Kritskiy O, Abdurrob F, Peng Z, Milo B, Yu CJ, Elmsaouri S, Dey D, Ko T, Yankner BA, Tsai LH. APOE4 Causes Widespread Molecular and Cellular Alterations Associated with Alzheimer's Disease Phenotypes in Human iPSC-Derived Brain Cell Types. Neuron. 2018 Jun 27;98(6):1141-1154.e7. Epub 2018 May 31 PubMed.
Narayan P, Sienski G, Bonner JM, Lin YT, Seo J, Baru V, Haque A, Milo B, Akay LA, Graziosi A, Freyzon Y, Landgraf D, Hesse WR, Valastyan J, Barrasa MI, Tsai LH, Lindquist S. PICALM Rescues Endocytic Defects Caused by the Alzheimer's Disease Risk Factor APOE4. Cell Rep. 2020 Oct 6;33(1):108224. PubMed.
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