Alzheimer's & Brain Awareness Month 2025: Looking Back at Recent Progress in Cell and Gene Therapy
In honor of Alzheimer's & Brain Awareness Month, observed annually in June, we took a look back at recent news and insights in cell and gene therapy for Alzheimer disease and other dementias.
According to the Alzheimer's Association, more than 55 million people across the globe currently live with Alzheimer disease (AD) or another dementia. Furthermore, 2 in 3 Americans possess 1 or more major potential dementia risk factor.
An emerging area of interest for the potential treatment of AD and other dementias is cell and gene therapy. A number of companies and academic institutions are now pursuing the development of these advanced modalities for such indications and several have made notable milestones in the past year. In honor of Alzheimer's & Brain Awareness Month, held annually in June, CGTLive® is taking a look back at some of the recent progress that has been made for cell therapy and gene therapy candidates in AD and dementia during the past year. Click the "READ MORE" buttons for more details and information about each item.
Longeveron's Cell Therapy Lomecel-B Improves Cognitive Function in Mild Alzheimer Disease
March 13, 2025 — New data from the now-completed phase 2a CLEAR MIND trial (NCT05233774), which is evaluating Longeveron's allogeneic bone marrow-derived medicinal signaling cell (MSC) formulation Lomecel-B (also known as laromestrocel) for the treatment of mild AD, have been published in Nature Medicine. Among the findings reported were improvements in cognitive function, quality of life, and brain volume.
The study included 48 patients, 36 of whom received laromestrocel and 12 of whom received a placebo. Longeveron reported that laromestrocel treatment was associated with a slowing in cognitive and functional decline. This finding was informed by statistically significant data from the Montreal Cognitive Assessment, as well as statistical trending improvements, made with comparison to the placebo group, on the Clinical Dementia Rating – Sum of Boxes (CDR-SB) and Mini-Mental State Examination (MMSE). Furthermore, Longeveron noted that on the Composite Alzheimer’s Disease Score (CADS), an improvement from baseline at 39 weeks posttreatment was recorded.
In addition, the company stated that on the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL), a statistically significant improvement was seen for the laromestrocel group in relation to the placebo group. Statistically significant data indicating that total brain volume, hippocampus volume, temporal and frontal lobe volumes, and thalamus volume losses had been minimized in the laromestrocel group compared to the placebo group were also noted. Improvements for the laromestrocel group in comparison to the placebo group were also observed on the the Alzheimer’s Disease Related Quality of Life (ADRQOL) and Quality of life AD (QOL-AD) scales.
NKGen’s Autologous NK Cell Therapy Troculeucel Fast Tracked for Alzheimer Disease
February 12, 2025 — NKGen Biotech's troculeucel (also known as SNK01), an investigational autologous natural killer (NK) cell therapy, has been granted fast track designation by the FDA for the treatment of moderate AD.
Troculeucel is currently being evaluated in a phase 1/2a trial (NCT06189963) for moderate AD. In May 2024, NKGen announced that the trial would be progressing to its phase 2 portion following clearance from a Safety Review Committee that looked at data from the phase 1 portion. The phase 2a portion is actively recruiting participants and NKGen anticipates that it will announce updated clinical data before the end of this year. Notably, troculeucel was originally developed for oncology indications and is also being evaluated for the treatment of Parkinson disease.
“We are pleased with the FDA’s decision to grant Fast Track designation for troculeucel,” Paul Y. Song, MD, the chairman and chief executive officer of NKGen, said in a statement. “This decision underscores the significant unmet need for effective treatments for patients with moderate AD. We specifically targeted the moderate stage population as they represent about 30% of all AD cases and most, if not all, of the current focus has been on early/mild patients. This designation comes after promising safety and efficacy results from our phase 1 trial, which shows early signs of clinical benefit in patients treated with troculeucel. Receiving fast track designation will significantly accelerate the drug development process, bringing us one step closer to delivering this promising therapy to AD patients in need, and ensuring faster access to a potentially life-changing treatment.”
Lexeo Therapeutics' Gene Therapy LX1001 Increases APOE2 Expression in Patients With Alzheimer Disease
November 4, 2024 — Lexeo Therapeutics' LX1001, an investigational adeno-associated virus (AAV) vector-based gene therapy, has demonstrated a dose- and time-dependent impact on apolipoprotein (APOE2) expression in patients with APOE4 homozygote Alzheimer disease (AD) in interim data from a phase 1/2, open-label clinical trial (NCT03634007). In addition, a decrease in several cerebrospinal fluid (CSF) AD tau biomarkers and changes on tau PET were reported.
The data were announced in a late-breaking presentation at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 29 to November 1, in Madrid, Spain. Fifteen patients were dosed in the trial across 3 ascending single-dose cohorts: 1.4x1010 gc/ml (C1; n = 5), 4.4x1010 gc/ml (C2; n = 4), 1.4x1011 gc/ml (C3; n = 3). A single fixed-dose cohort was also included, treating patients at a dose of 1.4x1014 gc (C4; n = 3). Participants in the 52-week study were administered prednisone for 8 weeks after treatment with LX1001. APOE4 homozygous status, an age of at least 50 years, positive amyloid PET, CSF biomarkers consistent with AD, and mild cognitive impairment or mild to moderate dementia due to AD were requirements for inclusion in the study.
In terms of safety, the gene therapy was deemed safe and well-tolerated, with no cases of amyloid-related imaging abnormalities (ARIA) reported. Expression of APOE2 in the CSF was observed in all of the patients, with a dose- and time-dependent increase in APOE2e4 expression noted. A decrease in CSF t-tau and phosphorylated-tau181 in 9 of the 13 participants was observed, although no directional trend in CSF amyloid-ß42/40 or amyloid PET was recorded. Notably, a decrease in CSF p-tau217 and p-tau231 was also seen in the 9 aforementioned patients.
NK Cells in Neurological Disorders: A New Frontier in Brain Disease Therapy
December 19, 2024 — In a preliminary published report, the intravenous delivery of NK cells weekly for 5 weeks in AD model mice has shown reduced microglial activation, reduced amyloid precursor protein deposits, and reduced cognitive decline.10 These data further support a role of NK cells in AD. The logical next horizon is to potentiate the neurological specificity of these NK cells with a strategic CAR.
This growing understanding of NK cells' role in AD is paralleled by emerging research into their potential therapeutic effects in other neurological conditions, such as Parkinson disease.
Passage Bio Gets Positive Feedback From FDA on Plans to Test Gene Therapy PBFT02 in New Frontotemporal Dementia Indication
July 19, 2024 — Passage Bio has received positive feedback from the FDA regarding its plans to expand eligibility for its phase 1/2 upliFT-D clinical trial (NCT04747431), which is currently evaluating investigational gene therapy PBFT02 in patients with frontotemporal dementia (FTD) with GRN mutations (FTD-GRN), to patients with FTD with mutations in the C9orf72 gene (FTD-C9orf72).
Passage Bio received the feedback on the proposal to amend the upliFT-D protocol in the context of a Type C meeting process with the FDA. The company stated that attainment of the agency’s alignment on the matter was supported by preclinical evidence, along with efficacy and safety data from patients with FTD-GRN who were treated in the first cohort of upliFT-D. In light of the FDA’s feedback, Passage Bio intends to submit a revised trial protocol to relevant regulatory bodies and ethics committees shortly. Pending clearance, the company anticipates that it may begin dosing patients with FTD-C9orf72 in upliFT-D within the first half of next year.
Notably, both FTD-GRN and FTD-C9orf72 are associated with a pathological accumulation of transactive response DNA binding protein 43 in neuron cytoplasm. PBFT02, which utilizes an adeno-associated virus 1 vector, is intended to deliver a functional copy of the GRN gene, which encodes for the protein progranulin (PGRN). The gene therapy is administered via intracisterna magna injection with the intention of increasing levels of PGRN in the central nervous system.
