From Our 2022 Familial Conference: Emerging Therapies in FTD-ALS Spectrum Disorders
The keynote presentation for the 2022 Familial FTD/ALS Conference was given by Drs. Lauren Elman and David Irwin, two active physician-researchers here at Penn.
Dr. Elman began by reviewing the basic outline for target therapy trials:
Identify a potential treatment target
Create a drug
Test drug safety in humans in a phase 1/2a trial
Move to an open label extensive trial and then to a phase 3 trial
The first target identified for ALS therapy trials was the SOD1 gene, which occurs in about 2% of all ALS cases. The drug Tofersen was created to target SOD1 and a phase 1/2a trial began. In Phase 1/2a, higher levels of Tofersen were associated with lower SOD protein levels in the cerebrospinal fluid (CSF), indicating a promising effect. Thus, Tofersen was approved for a 6-month phase 3 trial, however the phase 3 data did not show a significant difference in patient outcomes. Though disheartening, there is still hope. These data tell us that it may take longer than the 6-month trial duration for the drug to be effective. The ongoing open-label extensive theorizes that individuals that show slow symptom progression could potentially show significant positive outcomes after long term exposure to the drug.
The next genetic target Dr. Elman discussed was the chromosome 9 open reading frame 72 (C9orf72) gene. C9orf72 is responsible for about 40% of genetic ALS cases and about 7% of sporadic cases. The drug ASO was created, which degrades the messenger RNA at C9orf72 to prevent the production of the abnormal protein that leads to ALS. ASO has nearly completed the phase 1 trial with an ongoing open label extensive trial. In addition to C9orf72, ASO has a second genetic target, ATXN2 (a polyglutamine extension) that is the cause of about 2-4% of ALS cases. As in C9orf72, ASO degrades the messenger RNA to reduce ataxin 2 protein levels. The phase 1 trial for ASO to target ataxin 2 is also underway.
Even though we don’t have a current treatment for ALS, we have some powerful tools that are allowing us to create even more advanced trials. Dr. Elman finishes by explaining that the biggest successes to “treat” genetic ALS may come with treating individuals before they begin experiencing symptoms.
Next, Dr. Irwin addressed treatment of FTD. Scientists have identified many genes that can cause FTD, although three make up the majority of genetic forms of FTD. These 3 mutations each have a unique pathology and mechanism to be targeted in therapeutic trials. First, MAPT causes a hereditary form of FTLD-tau. Normally, tau proteins stabilize microtubules so neurons can function normally. In someone with a mutation in their MAPT gene, abnormal proteins are made causing tau to accumulate. This makes the microtubules unstable, resulting in the neurofibrillary tangles that cause FTLD-MAPT. Next is GRN hereditary FTLD-TDP. A mutation in the GRN gene causes abnormal progranulin (GRN) levels leading to a buildup of TDP-43 protein. Finally, the most common FTD genetic mutation is a repeat expansion within the C9orf72 gene that Dr. Elman talked about. The disruption of normal C9orf72 can lead to either FTD, ALS, or a combination of the two.
Dr. Irwin highlighted some of the incredible therapeutic trials for FTD for these targets. Here at Penn there are active studies to evaluate GRN-targeted therapies. Moreover, there are plans to soon begin a C9orf72-targeted therapy, a tau-targeted intervention for PSP patients, and an anti-inflammatory drug for svPPA patients.
In addition to genetic targets, Dr. Irwin emphasizes that FTD treatments would need to target tau and TDP proteins for sporadic (non-familial) cases. However, before we create a treatment to target either tau or TDP pathology, we need biomarkers that can let us diagnose underlying pathology for FTD patients in life. This is one of the goals of our observational research studies at Penn, so that more people may be eligible for treatment trials in the future.