Alzheimer Disease Awareness Month 2024: Looking Back at a Year of Progress in Cell and Gene Therapy

According to Alzheimer's Foundation of America, more than 6.9 million Americans currently live with Alzheimer disease (AD), and this number is expected to grow to 13.8 million by 2060. In addition, over 11 million Americans currently act as caregivers for people with AD, with estimates of time spent providing unpaid care totaling over 18.4 billion hours.

Cell therapy and gene therapy constitute an emerging area of interest for the potential treatment of AD, and a number of companies and academic institutions are now pursuing the development of a range of these advanced therapeutics for the disease. In honor of Alzheimer Disease Awareness Month, observed annually in November, CGTLive® is taking a look back at some of the progress that has been made for cell therapy and gene therapy candidates in AD over the past year. Click the "READ MORE" buttons for more details and information about each item.

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 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.

Lomecel-B Safe, Seems Promising for Alzheimer Disease Measures

July 29, 2024 — Lomecel-B was well-tolerated in patients with mild AD receiving up to 4 infusions of the cell therapy and demonstrated some improvements in cognitive function and other disease measures, according to new data from the phase 2a CLEAR MIND trial (NCT05233774).

These data were presented at the 2024 Alzheimer’s Association International Conference (AAIC), held July 28-August 2nd in Philadelphia, Pennsylvania, by Brian G. Rash, PhD, vice president, research and discovery, Longeveron.

The data are from 49 participants: 12 in the placebo arm, 13 in the low dose arm (1 dose x 25 million), 13 in the low, multi-dose arm (4 doses x 25 million), and 11 in the high, multi-dose arm (4 doses x 100 million). The therapy was well-tolerated, with no serious adverse events (AEs) related to Lomecel-B. Serious AEs that did occur included acute respiratory failure, anemia, lumbar radiculopathy, all of which resolved. There were no early discontinuations of infusion or any evidence of amyloid-related imaging abnormalities (ARIA).

NKGen’s Autologous NK Therapy Proceeds to Phase 2 Trial for Alzheimer Disease

May 20, 2024 — NKGen Biotech is progressing its clinical trial of SNK01 natural killer cell (NK) therapy into a phase 2 trial in people with AD. The announcement comes after a safety review committee reviewed data from the phase 1 portion of the trial and an internal review board cleared the program to continue.

“I am encouraged by the continued promise of NKGen’s SNK01 NK cell therapy in a difficult to treat disease such as AD,” Jesse Carr, MD, Medical Director, Behavioral Research Specialists, Glendale, California, who is independently overseeing the trial site, said in a statement. “We are seeing remarkable preliminary clinical benefit in all patients without treatment-related adverse events, including apparent improvements in cognitive function, increases in daily living activities and overall quality of life. I look forward to the potential that this novel drug candidate holds as we continue to progress the trial.”

SNK01 is an autologous NK cell therapy that is not genetically engineered but has enhanced cytotoxicity and activating receptor expression. The therapy has previously been assessed in the proof-of-concept phase 1 ASK-AD trial (NCT04678453) with a different manufacturing process. The study was an open label, 3+3 dose escalation study which demonstrated that 4 doses of 1, 2, or 4 billion SNK01 cells administered intravenously was safe and crossed the blood brain barrier to reduce amyloid, tau, and alpha-synuclein proteins. Investigators also observed a dose-dependent decrease in neuroinflammation and 90% of patients had improvements or maintenance in cognitive function as assessed by Alzheimer's disease composite score (ADCOMS).

Trial for Regeneration Biomedical’s Alzheimer Disease Stem Cell Therapy Doses First Patient

April 27, 2024 — The first patient has been dosed in Regeneration Biomedical’s phase 1 clinical trial (NCT05667649) for RB-ADSC, an autologous, Wnt-activated adipose-derived stem cell therapy, for the treatment of AD.

The first-in-human, open-label, single-arm trial is expected to enroll 9 participants over the course of a year, to be treated in a 3+3 dose escalation manner. The trial will evaluate safety and seek to establish a recommended dose for a possible phase 2 trial, with AD clinical assessments and evaluations of biochemical and anatomical biomarkers serving as secondary outcome measures. The study is recruiting patients aged 45 to 80 years of age with mild-to-moderate AD, with plans to follow patients for up to 12 months posttreatment.

“The first patient in this trial was dosed in March 2024, and no side effects or adverse events have been reported to date,” Gustavo Alva, MD, the principal investigator of the trial, said in a statement. “Enrollment is ongoing and we look forward to completing the trial and sharing its results. In phase 2, we plan to use the same cells for other diseases with unmet or poorly met needs such as multiple sclerosis, Parkinson disease, traumatic brain injury and amyotrophic lateral sclerosis.”

Epilepsy Cell Therapy NRTX-1001 May Eventually Be Evaluated for Alzheimer Disease

February 3, 2024 — Neurona Therapeutics’ allogeneic regenerative neural cell therapy, NRTX-1001, is currently only cleared by the FDA for investigational use in mesial temporal lobe epilepsy. As such, patients with other forms of epilepsy are unable to participate in the first-in-human phase 1/2 clinical trial (NCT05135091). Although, the company has plans to eventually evaluate NRTX-1001 in other epilepsy indications in future clinical trials, pending regulatory clearance.

In December 2023, following the presentation of data from the trial at the Annual Meeting of the American Epilepsy Society (AES), held December 1-5, 2023, in Orlando, Florida, CGTLive interviewed Cory R. Nicholas, PhD, the cofounder and CEO of Neurona Therapeutics, about challenges in the trial and future plans for the cell therapy product. Nicholas spoke potential future trials that could include patients with bilateral temporal lobe epilepsy, focal cortical dysplasias, and even AD that has epileptic-type activity.

REFEENCE
1. Facts About Alzheimer's Disease. Alzheimer's Foundation of America. Website. Accessed November 25, 2024. https://alzfdn.org/wp-content/uploads/2024/10/PRINT2024_Facts-About-Alzheimers-Disease-10.20.pdf