Current status of gene therapy for APOE-4 homozygotes

As we all know by now, finding an effective treatment for Alzheimer’s disease has not been easy.  Our best results so far are two anti-amyloid monoclonal antibodies, lecanumab (Leqembi) and donanemab (Kizuna). They are both very effective at removing beta-amyloid plaques from the brain, but they offer only slight slowing of the rate of cognitive decline, on average about 35%, not much better than the cholinesterase inhibitors like donepezil (Aricept). Interestingly, people who have two copies of the apolipoprotein E-4 allele (APOE-4) are not only less likely to benefit from anti-amyloid monoclonal antibodies, they generally have earlier onset of disease and a much greater chance of having potentially lethal side effects of brain swelling and/or bleeding (ARIA-e and ARIA-h) when they take anti-amyloid monoclonal antibodies. So what is an APOE-4 homozygote, like me, to do? It is becoming increasingly apparent that APOE-4 homozygotes are more likely to die from ARIA side effects than to benefit from anti-amyloid monoclonal antibodies. It’s time to think outside the box. 

Recall that there are three distinct alleles of the gene coding for apolipoprotein E.  APOE-2 is the least common, but interestingly it is markedly protective. APOE-2 homozygotes very rarely get Alzheimer’s disease. APOE-3 is the most common allele and it confers intermediate risk of Alzheimer’s. APOE-4 is more common than APOE-2 and less common than APOE-3, and it is associated with the highest risk of getting Alzheimer’s.  So what if you could alter the DNA of an APOE-4 homozygote by splicing APOE-2 DNA into his or her brain? Sound fantastic? It has recently been done by Lexeo Therapeutics. The results look promising.

LX1001 is Lexeo Therapeutic’s AAVrh10-based gene therapy designed to deliver the protective APOE-2 DNA into the brains of human APOE-4 homozygotes who, like me, have two copies of the toxic APOE-4 allele. Fifteen patients with mild cognitive impairment (MCI) or mild or moderate Alzheimer’s were injected through spinal taps with LX1001 in four dose-ascending groups. The study’s primary objective was to assess safety and tolerability, with secondary outcomes including cerebrospinal fluid (CSF) APOE-2 protein expression and change in tau and amyloid biomarkers. Results released in a press release showed (with minor edits):

• CSF APOE-2 protein expression was seen in all subjects proving that the injected DNA was indeed being incorporated and transcribed 
• Amyloid pathology was stabilized in the majority of participants, with minimal change from baseline in Aß42/40 ratio and amyloid PET
• Consistent reductions of CSF tau biomarkers including CSF T-tau, P-tau181, P-tau217 and P-tau231, in over two thirds of participants 
• Reductions at 6 months in global tau PET SUVR in 5 of 6 subjects
• Participants with moderate Alzheimer’s (n=4) generally demonstrated the most improvement across various biomarker endpoints
• Four  adverse events occurred, with three deemed unrelated to treatment and one event of moderate hearing loss assessed as possibly related to treatment.

Lexeo has two additional gene therapy candidates in preclinical development. LX1021 expresses APOE-2 with the protective Christchurch mutation. LX1020 combines APOE-2 expression with microRNA-mediated suppression of APOE-4. The prospect of gene manipulation to treat Alzheimer’s disease is tantalizing, but there are still many questions. So far there has been no data released about cognitive improvement or worsening. Biomarker improvement does not insure real life cognitive changes. What about cost? Other gene therapies are extremely expensive.  Most cost between  $1,000,000 and $4,000,000 (see graph below from Drug Discovery & Development).  Would I volunteer to enter a trial of LX1001 or a similar genetic therapy for Alzheimer’s? I am probably too advanced in my Alzheimer’s journey to be a good research candidate, but I would seriously consider it if offered the chance.