Species: Mouse
Genes: MAPT, MAPT-AS1, Mapt
Modification: MAPT: Knock-In; MAPT-AS1: Knock-In; Mapt: Knock-Out
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy
Strain Name: B6J.B6N-Tc(HSA17)1Mdk/J
Summary
MAPT(H2.1)-GR mice are among a series of models developed by Michael Koob and colleagues at the University of Minnesota, collectively referred to as Gene Replacement – Alzheimer’s Disease (GR-AD) mice. In GR-AD mice, “genes of interest are precisely and completely replaced in the mouse genome by their full human orthologs, along with all known overlapping, co-regulated non-coding RNAs (Benzow et al., 2024).”
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: 13 Feb 2024
Further Reading
No Available Further Reading
Species: Mouse
Genes: MAPT, MAPT-AS1, Mapt
Modification: MAPT: Knock-In; MAPT-AS1: Knock-In; Mapt: Knock-Out
Disease Relevance: Frontotemporal Dementia
Strain Name: B6J.B6N-Tc(HSA17*N279K)1Mdk/J
Summary
MAPT(H1.0*N279K)-GR mice are among a series of models developed by Michael Koob and colleagues at the University of Minnesota, collectively referred to as Gene Replacement – Alzheimer’s Disease (GR-AD) mice. In GR-AD mice, “genes of interest are precisely and completely replaced in the mouse genome by their full human orthologs, along with all known overlapping, co-regulated non-coding RNAs (Benzow et al., 2024).”
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: 13 Feb 2024
Further Reading
No Available Further Reading
Species: Mouse
Genes: MAPT, MAPT-AS1, Mapt
Modification: MAPT: Knock-In; MAPT-AS1: Knock-In; Mapt: Knock-Out
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy
Strain Name: B6J.B6N-Tc(HSA17)2Mdk/J
Summary
MAPT(H1.0)-GR mice are among a series of models developed by Michael Koob and colleagues at the University of Minnesota, collectively referred to as Gene Replacement – Alzheimer’s Disease (GR-AD) mice. In GR-AD mice, “genes of interest are precisely and completely replaced in the mouse genome by their full human orthologs, along with all known overlapping, co-regulated non-coding RNAs (Benzow et al., 2024).”
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 Feb 2024
Further Reading
No Available Further Reading
Overview
Name: Pridopidine
Synonyms: ACR16, TV-7820, Huntexil, ASP2314
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis, Huntington's Disease, Parkinson's Disease
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Phase 2/3), Huntington's Disease (Phase 3), Parkinson's Disease (Inactive)
Company: Prilenia Therapeutics
Background
Pridopidine, formerly called huntexil, is a selective agonist of the sigma1 receptor, a molecular chaperone located in the endoplasmic reticulum in association with mitochondria. Sigma1Rs are highly expressed in the central nervous system, and regulate calcium signaling, ion channel function, and the ER stress response. In various experimental systems, sigma1R agonists have been reported to be neuroprotective by improving mitochondrial function and neurotropic signaling, clearing toxic proteins, and decreasing neuroinflammation. The companies NeuroSearch and then Teva Pharmaceuticals originally began developing pridopidine for Huntington’s disease; Prilenia took over the program in 2018.
In preclinical work, pridopidine was studied extensively in cell-based mouse models of Huntington's, and was also reported to show beneficial effects across models of ALS, Parkinson's, and Alzheimer's diseases (reviewed in Ryskamp et al., 2019). For example, in the PS1 knock-in mouse model of Alzheimer's, pridopidine rescued synaptic damage induced by Aβ42 (Ryskamp et al., 2019). It promoted synaptogenesis in primary neurons and improved spatial memory in APP/PS1 transgenic mice; it increased BDNF availability in a microfluidic model of striatal neurons, and it modified the disease phenotype but did not extend survival in an ALS mouse model (Estevez-Silva et al., 2022; Lenoir et al., 2022; Estevez-Silva et al., 2022). Effects facilitating autophagy in cell-based models have been reported, as well, as have effects on endoplasmic reticulum stress, and neuroprotective effects on retinal ganglion cells in glaucoma models (Wang et al., 2023; Shenkman et al., 2021; Geva et al., 2021).
Other compounds with sigma1R agonist activity are in clinical trials for Alzheimer's disease; they include blarcamesine, edonerpic, and the dextromethorphan formulations AVP-786, AVP-923, and AXS-05.
Pridopidine was originally postulated to act through dopamine receptors, and was therefore developed initially for the treatment of motor symptoms in HD. However, in vitro binding assays, as well as studies in preclinical models, showed its effects occur specifically through sigma1Rs (e.g., Ryskamp et al., 2017). In a human PET imaging study, at clinical doses, pridopidine selectively occupied a large fraction of sigma1Rs in the brain, and not D2/D3 receptors (Grachev et al., 2020).
Findings
Based on its dopaminergic activity, pridopidine was originally tested to treat symptoms of Huntington’s disease. In a Phase 2 study of 58 patients, four weeks of 50 mg/day improved voluntary motor symptoms, including balance, gait, and hand movements, compared to placebo (Lundin et al., 2010). The drug was deemed safe and well-tolerated.
Between 2008 and 2010, TEVA ran two larger studies. Beginning in April 2008, the Phase 3 MermaiHD trial compared six months of 45 or 90 mg pridopidine daily to placebo in 437 people with HD. The primary outcome was a modified motor score comprising a subset of items from the Unified Huntington Disease Rating Scale Total Motor Score that focused on voluntary movements. The Phase 2/3 HART study began in October 2008 to test doses of 10, 22.5 or 45 mg twice daily for 12 weeks against the same primary outcome of the modified motor score. In both studies, pridopidine was well-tolerated up to 90 mg, but did not affect the modified motor score (de Yebenes et al., 2011; Huntington Study Group, 2013). Both studies detected a three-point, nominally significant, improvement in the pre-specified endpoint of the UHDRS Total Motor Score with treatment.
An open-label extension to HART enrolled 118 people to receive 45 mg twice a day for up to five years. After three years, participants had declined in motor function as seen in previous observational studies (McGarry et al., 2017). At four and five years, 40 and 33 participants remained, respectively. Their total motor and functional scores stabilized, i.e., did not show the decline expected from historical controls (McGarry et al., 2020).
In February 2014, TEVA began PRIDE-HD, a 6-month Phase 2 trial testing higher doses of pridopidine, using the UHDRS-TMS as a primary outcome. The study included an open-label extension that ran for up to 2 years. The PRIDE-HD study compared twice-daily doses of 45, 67.5, 90, or 112.5 mg to placebo in 408 people with HD. Treatment was originally planned for six months, but a mid-trial change in protocol extended the placebo-controlled period to one year, and added UHDRS-Total Functional Capacity (TFC), which is measured annually, as a secondary endpoint to measure disease progression. The UHDRS-TFC is a 13-point scale that encompasses ability to work, handle finances, do domestic chores and activities of daily living, and care level.
A peer-reviewed paper reported no statistically significant effect compared to placebo of any dose on the primary motor symptoms outcome at six months; all dose groups showed numeric improvement from baseline (Reilmann et al., 2019). Serious adverse events seen most frequently in the pridopidine groups were falls, suicide attempts or ideation, head injury, and aspiration pneumonia. No dose response was observed. One death in the highest-dose group due to aspiration pneumonia was considered possibly related to study drug. On the functional outcome, the TFC showed a benefit for 45 mg pridopidine twice daily at one year in all randomized patients (p=0.0032). Post hoc analysis indicated the effect on TFC was strongest in the patients with early HD (TFC 7-13 p=0.0003) (McGarry et al., 2020). A safety analysis of electrocardiograms taken during this trial reported a concentration-dependent effect of pridopidil on QT-interval, but noted a favorable cardiac safety profile at the therapeutic dose of 45 mg twice daily (Darpo et al., 2023).
In October 2020, Prilenia started PROOF-HD. This Phase 3 trial compared 65 weeks of 45 mg twice-daily pridopidine to placebo in 480 people with early HD defined as a line UHDRS-TFC of seven or greater. The primary endpoint was change from baseline in UHDRS-TFC. The trial missed its primary endpoint, according to an April 2023 press release of top-line results. The company claimed effects of pridopidine were reduced by the concomitant use of Huntington’s medications. More results were presented at the May 2023 American Academy of Neurology annual meeting (news report).
Pridopidine was also tested to treat ALS, as part of the Phase 2/3 Healey Platform. This multicenter trial is testing four investigational treatments in a parallel, standardized platform protocol. In December 2020, the study began to enroll 160 participants in the pridopidine arm; they will be randomized to 24 weeks of 45 mg twice daily pridopidine or placebo in a 3:1 ratio. The primary outcome is disease progression measures on the ALS Functional Rating Scale-Revised. Secondary measures include changes in the ability to talk or swallow, respiratory function, muscle strength, and survival. On February 23, 2023, the company announced negative top-line results (press release). Pridopidine did not significantly change the primary endpoint of ALSFRS-R total score, or key secondary endpoints. The company claimed that the drug did slow decline on the ALSFRS-R, and decrease neurofilament light concentrations, in a subset of faster-progressing patients early in disease. Pridopidine improved quantitative speech measures in the group as whole. An open-label extension continues.
In July 2021, the FDA granted pridopidine orphan drug status for ALS (company press release). Meta-analyses are starting to compile pridopidine trial results (Mostafa Asla et al., 2021; Chen et al., 2021).
In May 2019, a Phase 2 study evaluating two doses of pridopidine for its effect on levodopa-induced dyskinesia in Parkinson's disease began enrolling for its target population of 135 (McFarthing et al., 2019). It had enrolled 23 participants when it was terminated in November 2020 due to the COVID pandemic; results are posted on Clinicaltrials.gov.
For details on pridopidine trials, see clinicaltrials.gov.
Last Updated: 30 May 2023
Further Reading
No Available Further Reading
Species: Mouse
Genes: Trem2
Modification: Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6(SJL)-Trem2em1Aduci/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+.
Synaptic Loss
Synapse loss, assessed by co-localization of the pre-synaptic marker bassoon and postsynaptic marker PSD95, by 12 months.
Gliosis
Similar numbers of Iba1-immunoreactive microglia in Trem2*R47HNSS and wild-type hippocampi and cortices, but differences in microglial morphology at 4 months that are gone by 12 months.
Changes in LTP/LTD
Impaired basal synaptic transmission and LTP, by 12 months.
Last Updated: 07 Aug 2023
Further Reading
No Available Further Reading
Species: Mouse
Genes: Trem2
Modification: Trem2: Knock-In
Disease Relevance: Alzheimer's Disease
Strain Name: B6.Cg-Trem2em4Adiuj/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+.
Last Updated: 22 Jul 2021
Further Reading
No Available Further Reading
Overview
Name: BIIB105
Synonyms: ION541
Therapy Type: DNA/RNA-based
Target Type: Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Discontinued)
Company: Biogen, IONIS Pharmaceuticals
Background
BIIB105 is an antisense oligonucleotide (ASO). It binds the mRNA for ataxin-2 and mediates its degradation, which results in lower ataxin-2 protein levels. BIIB105 was being developed to treat amyotrophic lateral sclerosis.
The rationale for targeting ataxin-2 in ALS is twofold. First, polyglutamine expansions in the ataxin-2 gene increase carriers' risk for ALS. Second, work in yeast and fly models found that ataxin-2 promotes aggregation and toxicity of the TDP-43 protein (Elden et al., 2010). TDP-43 pathology is seen in almost all cases of ALS and is considered a common endpoint in both genetic and sporadic forms of the disease. Thus, decreasing ataxin-2 expression with an ASO could potentially benefit most people with ALS.
In contrast, other ASOs in development for ALS target inherited mutations in SOD1 (tofersen), C9ORF72 (BIIB078), or FUS (ION363) and, as such, are applicable only to the minority of patients with those genetic causes.
In preclinical work, an ataxin-2 ASO made at Ionis extended survival and improved motor function in a mouse model of TDP-43 proteinopathy (Becker et al., 2017). The ASO also delayed onset of symptoms and improved motor function in a mouse model of spinal cerebellar ataxia caused by polyglutamine expansion of the ataxin-2 gene (Scoles et al., 2017; Scoles and Pulst, 2018).
Findings
In September 2020, Biogen began a Phase 1 study to evaluate the safety and tolerability of BIIB105. Seventy people with ALS, with or without polyglutamine expansions in ataxin-2, were randomized to receive one of four doses or placebo by intrathecal injection. The multiple dosing schedule called for three loading injections one day apart, and two maintenance injections on later days over six months. The primary outcome was adverse events, with pharmacokinetics as a secondary outcome. In 2022, the companies upgraded the trial, now called ALSpire, to Phase 1/2, increased enrollment to 99, and added efficacy endpoints as well as a long-term extension. Participants in the two-year, open-label phase were to receive two or three loading doses plus 25 maintenance doses. Secondary outcomes were updated to include changes in the plasma biomarker neurofilament light chain, as well as clinical progression measured by the revised ALS Functional Rating Scale, muscle strength, time to needing permanent breathing assistance, and time to death. The study, ongoing at 13 sites in the U.S., Canada, Italy, and the Netherlands, was set to run through July 2026.
On May 16 2024, Biogen and Ionis announced they would discontinue development of BIIB105, based on negative topline results from this study (press release). While BIIB105 significantly reduced CSF ataxin-2 protein levels compare to placebo, it did not affect plasma neurofilament light chain, or clinical measures of function, breathing, and strength. Biomarker and efficacy data were similar after more than 40 weeks of follow-up in the open-label extension. The most common adverse events were pain due to the injections, headache, and falls.
For details, see clinicaltrials.gov.
Last Updated: 20 May 2024
Further Reading
No Available Further Reading
Overview
Name: Ulefnersen
Synonyms: ION363, Jacifusen
Therapy Type: DNA/RNA-based
Target Type: Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Phase 3)
Company: IONIS Pharmaceuticals
Background
ION363 is an antisense oligonucleotide designed to reduce the production of a mutated, neurotoxic form of the Fused in Sarcoma (FUS) protein. FUS mutations have been identified as a cause of familial ALS and frontotemporal lobar degeneration. ION363 is delivered by intrathecal injection.
One study has implicated FUS mutations in Alzheimer’s disease. In a study of familial AD in China, an FUS variant was associated with cases in families with no other known dementia-causing genes (Zhang et al., 2020). FUS was also identified as a gene involved in mRNA splicing errors that occur in AD brain (Oct 2018 news).
Findings
No Phase 1 or 2 trials are registered for this therapy.
In 2019, Ionis and Columbia University Medical Center sought permission from the U.S. FDA for compassionate use of ION363 in Jaci Hermstad, a 26-year-old woman with ALS caused by the P525L FUS mutation. P525L causes an aggressive and rapidly fatal form of ALS that begins in childhood or early adulthood (Conte et al., 2012), and Hermstad’s identical twin had earlier died of the disease (Nature Medicine news report). That led the U.S. House of Representatives to pass Jaci’s Bill, which allowed doctors to administer the ASO before completing toxicology testing in rodents. According to her obituary, Hermstad received 12 injections of the drug, named Jacifusen, between June 2019 and March 2020 before dying from ALS on May 1, 2020. Clinical details were later published (Korobeynikov et al., 2022). At the start of the trial, Hermstad was unable to move around on her own and needed assistance breathing. ION363 dosing started at 20 mg, and reached a maximum of 120 mg monthly, with no adverse events. Through the course of injections, her rate of decline on the ALS-Functional Rating Score slowed. At autopsy, ION363 was detected widely throughout brain and spinal cord tissue, two months after the last infusion. Normal and P525L FUS protein levels were reduced compared to normal control tissue, to nearly undetectable levels. Pathological hallmarks of P525L FUS-ALS were likewise reduced, including FUS-positive neuronal cytoplasmic inclusions, insoluble aggregates of FUS and other RNA binding proteins, and nuclear FUS localization.
As of February 2020, two more patients had received ION363 at Columbia through compassionate use protocols. In March 2020, the same investigators received funding from the ALS Association and Project ALS to treat eight more patients (ALS Association news).
In June 2021, Ionis began a Phase 3 trial called FUSION, to treat up to 77 patients worldwide. Participants are age 11 and older, have ALS caused by a confirmed pathogenic mutation in FUS, and must not be on permanent ventilation at the time of enrollment. They receive spinal injections of ION363 or placebo every twelve weeks, after a loading dose at four weeks, for 61 weeks, followed by an 85-week open-label extension. Patients who have completed this course can receive ION363 for another three years, in hopes that this second extension will bridge the time until the drug is commercially available. The primary outcome is functional change in the revised ALS-Functional Rating Scale, and time to live free of ventilation. Secondary outcomes include quality of life, lung and muscle function, survival, and changes in the CSF biomarker neurofilament light chain. Conducted at 24 sites in North America, Europe, the United Kingdom, Taiwan, and Korea, the trial is expected to run through June 2026.
For details on ION363 trials, see clinicaltrials.gov.
Last Updated: 19 Mar 2024
Further Reading
No Available Further Reading
Overview
Name: GRF6021
Synonyms: AKST/GRF6021
Therapy Type: Other
Target Type: Inflammation (timeline), Other (timeline), Unknown
Condition(s): Parkinson's Disease Dementia
U.S. FDA Status: Parkinson's Disease Dementia (Phase 2)
Company: Alkahest, Inc., Grifols Biologicals Inc.
Background
GRF6021 is a proprietary plasma fraction, developed by Alkahest and manufactured by Grifols. Its development follows GRF6019, a fraction in Phase 2 testing for Alzheimer’s disease. This treatment approach grows out of mouse parabiosis studies indicating a rejuvenating effect of young blood on the aging brain (e.g., Nov 2009 news; May 2014 conference news), and clinical research infusing young adult plasma to treat age-related neurodegenerative disease (see Young Plasma). The rationale behind GRF6021 is that the components of young blood that counteract inflammatory and other degenerative processes in the brain can be enriched from pooled plasma and delivered as a standardized product. The manufactured plasma fractions have clotting factors and immunoglobulins removed, which improves their safety. Matching donor and recipient blood type is not required.
Findings
In November 2018, a six-month, Phase 2 trial began to test GRF6021 in people with Parkinson’s disease and mild cognitive impairment or Parkinson’s disease dementia. The 79 participants were randomized 2:1 to daily infusions of 250 mg GRF6021 or placebo for five consecutive days, followed by a second five-day dosing period three months later. The primary endpoint was safety. Secondary endpoints include measures of cognition, daily function and clinical severity. The trial, at 29 sites in the U.S., Australia, and France, finished in July 2020. According to results presented at the March 2021 AD/PD conference, the trial met its primary safety endpoint. No serious adverse events were attributed to GRF6021, and more than 80 percent of participants completed both infusion regimens. Headache and falls were more common in the GRF6021 group compared to placebo. The trial reported improvements in some secondary endpoints. The Montreal Cognitive Assessment and the PDQ-39 quality of life measure showed small but statistically significant improvements from baseline, while the placebo group did not change. Measures of executive function and digital clock drawing improved, but the changes did not reach statistical significance.
For details on GRF6021 trials, see clinicaltrials.gov.
Last Updated: 19 Jul 2021
Further Reading
No Available Further Reading
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