Stem cell and gene therapies

DNA helix forming inside a test tube
A clutch of gene therapies are moving into clinical testing for AD, but results have been patchy. (Getty Images)

Following after these drug-based candidates for AD is an ever-lengthening list of high-tech therapies based on stem cells and viral vectors that can be used to introduce new genes into patients’ cells.

Stem cells can grow into neurons, and so they have the potential to repair the degenerative brain damage caused by AD. Among the players in this area is Nature Cell Co. which is developing an investigational drug, AstroStem, based on mesenchymal stem cells (MSCs) extracted from patients’ fat tissues. The biotech is running phase 1/2 trials of AstroStem at a hospital in South Korea and three clinical centers in the U.S. Results were due to be revealed last year, but so far there’s no word on the data.

Another Korean biotech—Medipost—in January completed a phase 2a trial of its Neurostem MSC therapy derived from umbilical cord blood, conducted at Samsung Medical Center. Initial results suggest the therapy is causing amyloid plaques to disappear in some patients, but longer follow-up will be needed to gauge other effects.

Following after is Florida-based biotech Longeveron, which in December completed enrollment in a phase 1 trial of its MSC-based therapy sourced from the bone marrow of healthy adult donors. The company estimates the final trial results will be available in late 2020.

A clutch of gene therapies are also moving into clinical testing for AD, from small biotechs and academic groups, although results so far have been patchy.

Sangamo was an early mover in this category with CERE-110, a drug originally developed by Ceregene that used an adeno-associated virus (AAV) vector to deliver the gene for nerve growth factor into an area of the brain that degenerates in dementia. It was safe, but ineffective, and was dropped in 2015.

Other groups have pressed on, though, including Voyager Therapeutics, which has joined forces with AbbVie to develop an AAV therapy that would produce “vectorized” anti-tau antibodies within the brain, although this remains in very early development.

Among the clinical-stage gene therapy projects is a Cornell University program that focuses on the ApoE4 gene, long established as a risk factor for AD. About 25% of people have one copy of APOE4, which doubles the risk of getting early-onset AD, while 2% of the population have two copies, elevating the risk three- to five-fold.

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The team at Cornell’s Weill Medical College have tested a strategy to replace APOE4 with another version of the gene called APOE2 that doesn’t seem to carry this elevated risk. In fact, in people who have a copy of APOE4 and APOE2, the presence of the latter seems to mitigate the risk.

The phase 1 trial is treating 15 people with the AAVrh.10hAPOE2 gene therapy, focusing mainly on safety, with results due later in 2020. Intriguingly, this approach could be used as a preventive

measure in people at high risk of AD. Meanwhile, MIT scientists are exploring how gene-editing with CRISPR could convert APOE4 to APOE2 in situ.

Another group from the University of South Florida (USF) is working on a gene therapy targeting the protein beta-arrestin-2, which disrupts tau clearance in the brain, although that’s still at the animal testing stage.

Startup Telocyte, meanwhile, is proposing a gene therapy that would rebuild telomeres—genetic caps on the ends of chromosomes that shorten when cells divide—in brain glial cells. The company envisions using a viral vector to deliver a copy of the telomerase gene TERT into the central nervous system and restore healthy glial cell function.

Stem cell and gene therapies