Cell and Gene Therapies Emerge as Promising Avenues for Alzheimer's Disease Treatment
核心洞察
Several cell and gene therapies are under investigation for Alzheimer's disease (搜索), with some showing early signs of efficacy in clinical trials.
NKGen (搜索)'s SNK01, an autologous NK cell therapy, demonstrated encouraging clinical activity and tolerability in a Phase 1 trial, with improvements in ADCOMS scores and CSF α-syn levels.
Longeveron's Lomecel-B, an allogeneic MSC therapy, showed statistically significant improvements in ADCS-ADL scores and trends of improvement on MMSE in a Phase 2 trial.
The landscape of Alzheimer's disease (搜索) (AD) treatment is evolving, with cell and gene therapies (CGTs) emerging as potential game-changers. Affecting nearly 7 million people in the United States alone, AD was the fifth-leading cause of death among individuals aged 65 and older in 2021. While anti-amyloid therapies like aducanumab, donanemab, and lecanemab have entered the market, researchers are increasingly exploring CGTs to achieve more dramatic slowing or even halting of disease progression.
NK Cell Therapy Shows Promise
NKGen (搜索)'s SNK01, an autologous natural killer (NK) cell therapy, is currently in Phase 2 trials after receiving FDA clearance in May 2024. Unlike genetically engineered cell therapies, SNK01 utilizes patients' own NK cells, enhanced for cytotoxicity and activating receptor expression. According to Paul Y. Song, MD, chairman and chief executive officer of NKGen, SNK01 has demonstrated a strong safety profile across multiple trials, with no pretreatment required and excellent tolerability in patients.
Data from the Phase 1 ASK-AD trial (NCT04678453), presented at the 2024 Alzheimer’s Association International Conference (AAIC), revealed encouraging results. The study included 10 evaluable participants with a median age of 79 years who received intravenous SNK01 every three weeks for a total of four treatments, using a 3+3 dose escalation design (1, 2, and 4 x 10 cells). The therapy was well-tolerated, with no treatment-related adverse events observed.
Notably, even at lower doses, 90% of evaluable subjects had either stable or improved composite AD Composite Score (ADCOMS) scores at week 11, and 60% showed a decrease in cerebrospinal fluid (CSF) α-synuclein compared to baseline values. In 5 of 6 evaluable participants, decreases in α-syn correlated with stable or decreased ADCOMS.
Song noted that SNK01 appears to cross the blood-brain barrier, upregulating a chemokine receptor necessary for NK cell trafficking into the brain, potentially driving positive changes.
MSC Therapy Demonstrates Early Efficacy
Longeveron's allogeneic medicinal signaling cell (MSC) therapy, Lomecel-B, has also shown promise in treating AD. Data from the Phase 2 CLEAR-MIND trial (NCT05233774), presented at the AAIC meeting, indicated improvements in some disease measures. Joshua M. Hare, MD, FACC, FAHA, cofounder, chief science officer, and chairman of Longeveron, highlighted directional improvements in cognitive scores, suggesting potential for cognitive function enhancement in mild AD patients.
The CLEAR-MIND trial involved 49 participants across placebo, low-dose, low multi-dose, and high multi-dose arms. The therapy was well-tolerated, with no serious adverse events related to Lomecel-B. Treated participants exhibited better scores on Composite Alzheimer’s Disease Score (CADS), Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and AD Cooperative Scale-Activities of Daily Living (ADCS-ADL) compared to placebo. Specifically, participants in the high, multi-dose arm performed statistically significantly better on ADCS-ADL (P = .04) than placebo, with trends of improvement on MMSE. Participants in the low-dose arm performed statistically significantly better on MoCA (P = .009), with trends of improvement in CADS at 39 weeks.
The FDA has granted both Fast Track and Regenerative Medicine Advanced Therapeutic (RMAT) designations to Lomecel-B.
Hare also noted that Lomecel-B slowed atrophy in the hippocampus, a region heavily implicated in AD, and this slowing correlated with clinical improvements in cognitive scores.
Other Emerging Therapies
Beyond SNK01 and Lomecel-B, several other novel therapies are under investigation for AD. Biogen, the sponsor of aducanumab, is developing an antisense oligonucleotide (ASO) therapy, BIIB080, targeting tau (搜索). BIIB080 has entered Phase 2 trials and has demonstrated the ability to safely lower tau levels.
Other notable therapies in Phase 1 trials include AAV2-BDNF gene therapy, sponsored by the University of California, San Diego, and Regeneration Biomedical’s RB-ADSC, an autologous, Wnt-activated adipose-derived stem cell therapy.
Broader Treatment Landscape
While amyloid-targeting antibodies like lecanemab and donanemab have received regulatory approval, their benefits are modest, primarily slowing disease progression in early stages. Andrew Doig, a professor of biochemistry at the University of Manchester, noted that lecanemab delays progression to more severe dementia by about six months. However, these drugs carry risks, including amyloid-related imaging abnormalities (ARIA), which can cause brain hemorrhage.
Doig suggests that future research should focus on a wider range of targets beyond amyloid-beta (搜索), including tau (搜索), anti-inflammatories, and antivirals. Drug repurposing, such as using the shingles vaccine Shingrix or anti-obesity drugs like semaglutide, may also offer promising avenues for AD treatment.
Ultimately, the evolving treatment landscape for Alzheimer's disease (搜索) offers hope for more effective and targeted therapies in the future.