Overview
Name: Emtricitabine
Chemical Name: 2',3'-dideoxy-5-fluoro-3'-thiacytidine
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Gilead Sciences, Inc.
Background
This nucleoside analog reverse transcriptase inhibitor is used for the prevention and treatment of HIV infection. It is taken as capsules or an oral solution, and is always combined with other antiretrovirals. It is well tolerated, with mild to moderate diarrhea, headache, nausea, and rash being the most common side effects.
Interest in repurposing reverse transcriptase inhibitors (RTIs) to treat Alzheimer’s disease arose from studies implicating DNA retrotransposon activity in aging and neurodegeneration. Increasing retrotransposon activity with age leads to the accumulation of nuclei acids in the cytosol of cells. There, they activate the immune system and promote inflammation, a causative factor in age-associated diseases including neurodegeneration. Nucleoside RTIs have been shown to reduce inflammation in animal models and in human clinical trials (e.g. De Cecco et al. 2019; Rice et al., 2018). One study reported intrinsic anti-inflammatory activity of nucleoside RTIs, independent of reverse transcriptase (Fowler et al., 2014). Other RTIs are in trials for AD, amyotrophic lateral sclerosis/frontotemporal dementia, and progressive supranuclear palsy, due to their ability to quiet inflammation (TPN-101), or to modulate cholesterol metabolism (Efavirenz).
Findings
In December 2021, a Phase 1 safety study of emtricitabine began at Butler Hospital in Providence, Rhode Island. It is enrolling 25 people with biomarker-confirmed mild cognitive impairment or mild to moderate dementia due to AD to receive six months of either placebo or the standard HIV dose of 200 mg daily emtricitabine. The primary outcome is the number of people with adverse events due to treatment; secondary outcomes include levels of inflammatory biomarkers in blood, cognitive and functional scales, and CSF phospho-tau and Aβ42. The trial will run until March 2024.
For details on this trial, see clinicaltrials.gov.
Last Updated: 15 Sep 2023
Further Reading
No Available Further Reading
Overview
Name: Efavirenz
Synonyms: Efavirenz
Chemical Name: (4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-1H-3,1-benzoxazin-2-one
Therapy Type: Small Molecule (timeline)
Target Type: Amyloid-Related (timeline), Tau (timeline), Cholesterol
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Approved for: HIV infection
Background
Efavirenz is an FDA-approved anti-retroviral medication used for human immunodeficiency virus infection. A non-nucleoside reverse transcriptase inhibitor, it is taken in pill form. It can cause serious side effects, including changes in mental health, liver toxicity, and severe skin rash and allergic reactions. Interest in repurposing this drug for Alzheimer’s disease stems from the discovery that doses 100 times lower than used for HIV promote cholesterol efflux from the brain. Excess brain cholesterol, and altered cholesterol metabolism, are both implicated in AD.
Low-dose efavirenz lowers brain cholesterol by allosterically activating the enzyme cholesterol 24-hydroxlyase, also known as CYP46A1 (Mast et al., 2014). CYP46A1-mediated modification is the major pathway for eliminating excess cholesterol from the brain. In preclinical work, efavirenz lessened memory loss in 5XFAD mice, and reduced brain amyloid when started early (Petrov et al., 2019; Mast et al., 2017). Treatment was associated with changes in astrocyte and microglial activation, expression of synaptic proteins, and membrane properties (Petrov et al., 2019; Petrov et al., 2020). This work was all done in one lab, but it is supported by previous studies on modulation of Aβ and tau pathology by CYP46A1 and cholesterol metabolism (e.g., see Djelti et al., 2015; Hudry et al., 2010; Burlot et al., 2015).
Efavirenz was independently identified in an unbiased screen for phospho-tau-lowering drugs using neurons derived from Alzheimer’s patient stem cells (Feb 2019 news on van der Kant et al., 2019). In this system, reduction of the abundance of cholesterol esters promoted phospho-tau degradation by the proteasome. The drug also reduced Aβ42 production, but by a different mechanism involving cholesterol binding to the amyloid precursor protein. In another study, efavirenz promoted uptake of tau seeds into cells, by changing the cholesterol makeup of cell membranes (May 2022 news on Tuck et al., 2022).
Efavirenz was reported to diminish the frequency of retinal vascular lesions in AD mice, suggesting a potential use in people with macular degeneration (El-Darzi et al., 2022). It prolonged the survival of prion-infected mice (Ali et al., 2021).
Findings
In May 2018, a Phase 1 trial began at two U.S. hospitals to test target engagement of efavirenz in people with Alzheimer’s disease and mild cognitive impairment or mild dementia. The study planned to enroll 36 patients for a 20-week course of 50 or 200 mg per day, or placebo. For comparison, the standard dose for HIV is 600 mg/day. The primary outcome was change in plasma 24-hydroxycholesterol, the product of CYP46A1 and a biomarker of brain enzyme activity. The study also aimed to assess CYP46A1 activity using "heavy water" Stable Isotope Labeling Kinetics (SILK) of plasma 24-hydroxycholesterol. The trial ended in January 2022, after enrolling only five patients. According to published results, 50 or 200 mg elicited a significant increase in plasma 24-hydroxycholesterol, which reversed after drug was stopped (Lerner et al., 2022). One patient on the 200 mg dose was evaluated with the SILK protocol, and showed evidence of increased brain cholesterol turnover consistent with CYP46A1 activation. The drug caused no serious side effects. One patient on the 50 mg dose withdrew after eight weeks treatment due to a diffuse skin rash, a known and common side effect of efavirenz. Low enrollment was attributed in part to the COVID-19 pandemic.
Investigators in the Netherlands said they are planning a Phase 2 trial to refine dosing based on plasma 24-hydroxycholesterol (see 2022 comment). No such trial has been registered to date.
For details on the Phase 1 trial, see clinicaltrials.gov.
Last Updated: 15 Sep 2023
Further Reading
No Available Further Reading
Species: Mouse
Genes: Plcg2, APP, PSEN1
Modification: Plcg2: Knock-In; APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
The PLCG2 gene encodes the enzyme phospholipase C gamma 2 (PLCγ2), a mediator of transmembrane signaling in microglia that acts downstream of TREM2.
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
Diffuse and compact amyloid plaques observed in mice studied at 7.5 months of age. Lower plaque burdens than 5xFAD.
Synaptic Loss
No deficits in synaptic transmission—including basal synaptic transmission, frequencies and amplitudes of spontaneous excitatory postsynaptic currents and spontaneous inhibitory postsynaptic currents, and AMPA/NMDA current ratios—recorded in hippocampal CA1 region of 7.5-month-old mice.
Gliosis
Microgliosis observed in mice studied at 7.5 months of age.
Changes in LTP/LTD
Normal LTP at Schaffer collateral-CA1 synapses at 7.5 months of age.
Cognitive Impairment
Normal working memory (spontaneous alternation in the Y-maze) at 6 months of age.
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: Plcg2, APP, PSEN1
Modification: Plcg2: Knock-In; APP: Transgenic; PSEN1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
The PLCG2 gene encodes the enzyme phospholipase C gamma 2 (PLCγ2), a mediator of transmembrane signaling in microglia that acts downstream of TREM2.
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
Diffuse and compact amyloid plaques observed in mice studied at 7.5 months of age. Higher plaque burdens than 5xFAD.
Synaptic Loss
Decreased basal synaptic transmission, lower frequencies and amplitudes of spontaneous excitatory postsynaptic currents and spontaneous inhibitory postsynaptic currents recorded in hippocampal CA1 region, compared with wild-type mice.
Gliosis
Microgliosis observed in mice studied at 7.5 months of age.
Changes in LTP/LTD
Impaired LTP at Schaffer collateral-CA1 synapses, compared with wild-type.
Cognitive Impairment
Deficits in working memory (decreased spontaneous alternation in the Y-maze), compared with wild-type.
Last Updated: 11 Sep 2023
Further Reading
No Available Further Reading
Species: Mouse
Genes: TREM2
Modification: TREM2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: C57BL/6-Trem2em2(TREM2*R47H)Aduci/J
Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a transmembrane receptor that modulates microglial activity and survival. A rare variant in TREM2, R47H, triples the risk of Alzheimer’s disease in heterozygous carriers.
This knock-in model carries a “humanized” TREM2 gene with the R47H mutation.
The levels of expression of the humanized allele and wild-type mouse allele are similar in heterozygous mice, as assessed by RNA-Seq of the hippocampi and cortices from 2-month-old animals.
Both heterozygous and homozygous mice are viable and fertile.
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: 14 Aug 2023
Further Reading
No Available Further Reading
Species: Mouse
Genes: TREM2
Modification: TREM2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: C57BL/6J-Trem2em3(TREM2)Aduci/J
Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is a transmembrane receptor that modulates microglial activity and survival. A rare variant in TREM2, R47H, triples the risk of Alzheimer’s disease in heterozygous carriers.
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: 15 Aug 2023
Further Reading
No Available Further Reading
Overview
Name: AAV-GAD
Synonyms: AAV-GAD2, NLX-P101
Therapy Type: DNA/RNA-based
Target Type: Other Neurotransmitters (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 1/2)
Company: MeiraGTx Limited
Background
AAV-GAD is a gene therapy for Parkinson’s disease. It delivers the glutamic acid decarboxylase (GAD) gene to the subthalamic nucleus, where this enzyme then increases production of the inhibitory neurotransmitter γ-amino-butyric acid (GABA). In people with Parkinson’s disease, increased activity of subthalamic nucleus neurons due to loss of inhibitory input contributes to movement problems such as tremor, rigidity, and difficulty walking. The goal of GAD gene therapy is to boost levels of GABA and normalize activity of these neurons. This is a similar mechanism to subthalamic deep brain stimulation, an approved surgical treatment for Parkinson’s symptoms.
The therapy, originally developed at Neurologix Inc., consists of a 1:1 mixture of two adenovirus vectors encoding the GAD-65 and GAD-67 enzyme isoforms, under regulation of cytomegalovirus enhancer–chicken β-actin promoter and woodchuck posttranscriptional regulatory elements. It is a given as a one-time injection, utilizing a surgical procedure similar to the implantation of deep brain stimulation (DBS) electrodes.
In preclinical work in rats, AAV-GAD injection into the subthalamic nucleus on one side led to robust GAD expression on the injected side five months later, but not on the uninjected side. In a toxin-induced Parkinson’s model, AAV-GAD-treated animals maintained significantly higher levels of GABA, better movement, and more dopamine neurons (Luo et al., 2002). An independent group showed efficacy of an AAV-GAD65 vector in Parkinson’s rats (Kim et al., 2008). The gene therapy was safe and improved some motor symptoms in a rhesus monkey model of Parkinson’s (Emborg et al., 2007). In a safety study performed in rats, AAV-GAD was not detected in blood or CSF after subthalamic injection. The vector did not disseminate to any organs outside the brain in most animals, or cause changes in general health or behavior (Fitzsimons et al., 2010).
Findings
In August 2003, Neurologix Inc. began a first-in-human study in 12 Parkinson’s patients, who received one of three doses of AAV-GAD into the subthalamic nucleus on one side of the brain. The surgical infusions caused no complications or adverse effects. The patients improved on the Unified Parkinson’s Disease Rating Scale (UPDRS) for motor function starting three months after surgery. Improvement was predominantly on one side, and persisted out to the one-year follow-up. FDG-PET imaging revealed reduced glucose utilization in the thalamus on the treated side one year after surgery (Kaplitt et al., 2007). Additional analysis of FDG-PET data showed that treatment caused normalization of metabolic activity in a motor-related brain network involving the subthalamic region and motor cortex, that correlated with clinical improvements (Feigin et al., 2007).
Phase 2 began in August 2008, with a placebo-controlled study in 44 advanced PD patients. Treatment consisted of bilateral virus injections, or control saline infusion. The primary outcome was listed as change in UPDRS scores. A long-term follow-up was to run for five years, but the study was terminated in December 2010 for financial reasons.
Results of this trial are published. Six months after treatment, motor scores while off dopamine medication improved in the treatment group by 23.1 percent, compared to just 12.7 percent improvement in the placebo group. While a positive result, the improvement was less than typically achieved with deep-brain stimulation. Adverse events were mild or moderate, with the most common being headache and nausea, likely related to surgery (LeWitt et al., 2011). At one-year post-surgery, motor scores were still better in treated patients compared to placebo. Treatment reduced the daily duration of levodopa-induced dyskinesias. FDG-PET showed glucose uptake declining in the thalamus, striatum, and cortical regions, suggesting an attenuation of hyperactivity in the subthalamic nucleus (Niethammer et al., 2017).
In early 2012, Neurologix cancelled a planned Phase 3 trial and declared bankruptcy.
In 2018, the publication of more FDG-PET data from the Phase 2 study revived interest in AAV-GAD, which had been acquired by MeiraGTx (press release). The gene therapy appeared to stimulate new functional connections in the brain, and these new circuits correlated with clinical efficacy (Niethammer et al., 2018). These changes were not seen in control or DBS-treated patients.
In October 2022, MeiraGTx restarted development with a Phase 1/2 placebo-controlled study in 14 people with Parkinson’s disease. Treatment will be a single bilateral infusion of two different doses of AAV-GAD or sham surgery, against a primary outcome of adverse events. The trial will also measure symptoms on the MDS-UPDRS motor function scale in the off-medication state at three and six months after surgery. The trial, at four sites in the U.S., will run until March 2024.
AAV-GAD has Fast Track designation from the U.S. FDA.
For details on AAV-GAD trials, see clinicaltrials.gov.
Last Updated: 26 May 2023
Further Reading
No Available Further Reading
Overview
Name: CpG 1018®
Synonyms: CpG oligodeoxynucleotides, CpG ODN
Therapy Type: Immunotherapy (active) (timeline), DNA/RNA-based
Target Type: Amyloid-Related (timeline), Inflammation (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Dynavax Technologies
Background
CpG 1018 is a proprietary immune adjuvant made up of short, unmethylated cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODNs). Its components mimic bacterial DNA to activate innate immunity through binding to the toll-like receptor 9 (TLR9). CpG 1018 is added to vaccines to enhance immune responses to protein antigens. TLR9 is also an important regulator of microglia, and CpG 1018 is being tested on its own for its potential to stimulate clearance of amyloid pathology and treat Alzheimer’s disease. It is given by subcutaneous injection, and does not enter the brain.
In early studies, CpG ODNs stimulated the uptake of Aβ by mouse microglia (Iribarren et al., 2005). More recently, New York University researchers showed that CpG ODN treatment reduced Aβ and tau pathologies, and improved performance on cognitive tests, in the Tg2576 mouse amyloidosis model (Scholtzova et al., 2009; Scholtzova et al., 2014). CpG ODN stimulated clearance of vascular amyloid and improved cognition in Tg-SwDI mice, without causing microhemorrhages (Scholtzova et al., 2017). In old squirrel monkeys, a nonhuman primate model of sporadic Alzheimer’s disease, two years of subcutaneous CpG ODN injections reduced vascular amyloid and phosphorylated tau in brain, and improved behavior, without inducing microhemorrhages or inflammatory responses (Patel et al., 2021).
CpG 1018 is a component of several approved vaccines, including hepatitis B and COVID vaccines.
Findings
In March 2023, CpG 1018 began a Phase 1 safety trial in 39 people with amyloid PET-confirmed early Alzheimer’s disease. Participants in the ascending dose study will receive three subcutaneous injections, three weeks apart, of 0.1, 0.25, or 0.5 mg/kg, or placebo. Dosing cohorts will proceed sequentially, with higher doses commencing after safety confirmation of the preceding dose. Primary outcomes are adverse events, levels of various autoimmunity markers in blood, and ARIA-E or -H on MRI. Secondary outcomes include change in the ADAS-COG13, ADCS-ADL, CDR, and MoCA, as well as amyloid and tau CSF and plasma biomarkers. Funded by the Alzheimer’s Association, the trial is taking place at New York University, with completion anticipated in November 2024.
Dynavax is also evaluating CpG 1018-containing vaccines for pneumonic plaque, TDaP, and shingles.
For details on CpG 1018 trials, see clinicaltrials.gov
Last Updated: 26 May 2023
Further Reading
No Available Further Reading
Overview
Name: VGL101
Synonyms: Iluzanebart
Therapy Type: Immunotherapy (passive) (timeline)
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia
U.S. FDA Status: Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (Phase 2)
Company: Vigil Neuroscience, Inc.
Background
VGL101 is a humanized monoclonal antibody that acts as an agonist for TREM2. This receptor is expressed on microglia and macrophages, and mediates their proliferation and function. VGL101 is claimed to activate TREM2 signaling with sub-nanomolar potency and selectivity. While other TREM2 agonist antibodies are in trials for Alzheimer’s disease, Vigil is developing VGL101 for the treatment of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). A rare and fatal neurodegenerative disease, ALSP is caused by mutations in the gene for the glial protein Colony Stimulating Factor 1 Receptor (CSF1R), which shares a common downstream signaling pathway with TREM2. The rationale for VGL101 is that TREM2 activation should compensate for loss of CSFR1 function and rescue glia function.
Vigil licensed this antibody from Amgen, which had published preclinical work on TREM2 antibodies that activated signaling and abrogated defects in microglia carrying the rare R47H TREM2 gene variant, a risk factor for AD (Cheng et al., 2018). Amgen’s monoclonal antibody hT2AB activated microglia in 5XFAD mice with R47H TREM2, but had limited efficacy in mice with the more common TREM2 variant (Ellwanger et al., 2021).
Vigil presented preclinical work on VGL101 in ALSP cell models at the August 2022 AAIC (abstract; poster). In human iPSC-derived microglia depleted of CSF1 or treated with a CSF1R kinase inhibitor, VGL101 stimulated TREM2 signaling, rescued cell viability, and promoted morphological changes consistent with microglia activation.
Findings
According to Vigil’s Securities and Exchange Commission filing, the FDA approved an Investigational New Drug application for VGL101 in November 2021, at doses up to 20 mg/kg. VGL101 subsequently entered Phase 1 in the U.S. with a single- and multiple-ascending-dose trial that does not appear in any of the common trial registries. In June 2022, the company announced it had expanded the trial to Australia, where it was allowed to test doses above the FDA limit (press release; trial details).
In November 2022, Virgil released interim data for Phase 1 (press release; slides). At the time of the report, the trial had enrolled 82 healthy volunteers who received single intravenous infusions of 1, 3, 10, 20, 30, or 40 mg/kg or placebo, or three 20 mg/kg infusions at monthly intervals. The antibody reportedly showed acceptable safety and tolerability at the highest doses tested. Pharmacokinetics were dose-proportional, with an antibody half-life of 27 days, and CSF concentrations reaching 0.1-0.2 percent of serum. Repeat administration led to dose-dependent decreases in CSF soluble TREM2 and increases in soluble CSF1R, indicating target engagement and pharmacodynamic effects.
Complete Phase 1 results of single and multiple dosing up to 60 mg/kg were presented at the September 2023 American Neurology Association meeting (press release). In 136 healthy volunteers, single or multiple doses up to 60 mg/kg were safe and tolerable, with pharmacokinetics sufficient for monthly dosing, the company said.
Phase 2 began in December 2022, with an open-label study in 20 people with ALSP and CSF1R mutations. Participants receive infusions of 20 or 40 mg/kg VGL101 every four weeks for one year. The primary outcome is adverse events; secondaries are brain volume on MRI, ALSP symptom severity scores, and the CSF biomarkers neurofilament light and CSF1R. The study is running at three sites in the U.S., and additional sites in France, Germany, Netherlands, and the U.K. . An optional long-term extension offers treatment for up to an additional two years.
The company is also conducting a two-year observational MRI study in 36 CSF1R mutation carriers, with and without symptoms. Completion of this natural history study is expected in November 2024.
In March 2023, Vigil announced that the FDA had removed the Phase 1 dose cap, after more preclinical and clinical data became available (press release).
In April 2024, Vigil presented interim Phase 2 results at the American Academy of Neurology annual meeting (slides). In six patients treated with 20 mg/kg for six months, soluble CSF1R and osteopontin biomarkers of microglial activity were increased, while the neurodegeneration biomarker NfL trended down. No treatment-related serious adverse events or discontinuations were noted.
The FDA has granted Orphan Drug and Fast Track designation to VGL101 for ALSP.
For details on the phase 2 VGL101 study, see clinicaltrials.gov.
Last Updated: 15 Oct 2024
Further Reading
No Available Further Reading
Overview
Name: AAV2-BDNF
Therapy Type: DNA/RNA-based
Target Type: Other (timeline)
Condition(s): MCI due to AD, Alzheimer's Disease
U.S. FDA Status: MCI due to AD (Phase 1), Alzheimer's Disease (Phase 1)
Background
This gene therapy uses an adeno-associated virus serotype 2 (AAV2) vector to carry a gene for human brain-derived neurotrophic factor into the brain. BDNF regulates neuron survival and function in key memory circuits in entorhinal cortex and hippocampus. In people with AD, BDNF is decreased. AAV2-BDNF attempts to restore normal levels of BDNF.
This program follows CERE-110, which attempted to deliver NGF via AAV (Mar 2018 news).
IIn early studies with mouse models of AD, BDNF gene therapy reversed synaptic loss, and restored learning and memory, without affecting amyloid plaque load (Nagahara et al., 2009; Nagahara et al., 2013). The same studies used rats and nonhuman primates to show that BDNF protein or lentivirus-BDNF delivered to the brain reduced age-related cognitive decline. Preclinical work with MRI-guided injection of AAV2-BDNF into the entorhinal cortex in nonhuman primates demonstrated elevation of BDNF protein in neurons of that region, and in the hippocampus, with no apparent safety issues (Nagahara et al., 2018; for review, see Tuszynski 2024).
Findings
In February 2022, Phase 1 began with an open-label study of this gene therapy in six volunteers with early Alzheimer’s, and six with mild cognitive impairment. Participants are to undergo one MRI-guided surgery to infuse AAV2-BDNF into the entorhinal cortex, followed by two years observation. Two doses are to be tested. Primary outcomes are the number of treatment-related adverse events, and memory changes measured on the Ray Auditory Verbal Learning Task and Benson Complex Figure Draw and Memory test. Secondary outcomes are change in FDG-PET, CSF biomarkers of amyloid, tau, and neurofilament, and MMSE ADAS-Cog. Sponsored by the University of California, San Diego, the study is underway there and at Ohio State University until October 2027.
Interim results were presented at the October 2024 CTAD conference. At that time, four subjects had safely completed gene delivery surgery. The first two received unilateral gene delivery to the right entorhinal cortex, and the other two were treated bilaterally. MRI confirmed accurate targeting and vector spread. No significant adverse events and no seizure activity were reported up to 15 months after treatment. In the first participant with FDG PET readings, the signal was increased by 14 percent on the treated side, and decreased in untreated regions. Surgical treatment of the AD patients will be complete in December 2024, and the MCI cohort is expected be completed in 2025.
For details on this trial, see clinicaltrials.gov.
Last Updated: 15 Nov 2024
Further Reading
No Available Further Reading
Comments
No Available Comments
Make a Comment
To make a comment you must login or register.