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Blocking a protein called PTP sigma led to better nerve survival and motor function in a mouse model of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) caused by mutations in the C9ORF72 gene — leading the researchers to highlight this strategy for potentially treating this genetic ALS form.
Data from cell models suggest that reducing PTP sigma is protective because it activates a molecular pathway used to transport molecular cargo within nerve cells, which is required to move unwanted proteins to sites of degradation, pointing to this pathway as a possible therapeutic target.
&#8220;These exciting findings highlight the role of [this pathway] in the [disease development of this ALS form], offering a new direction for the therapy development of the disease,&#8221; the scientists wrote in an abstract detailing the research findings.
Zhe Zhang, PhD, a postdoctoral fellow at Johns Hopkins University, in Maryland, presented the findings in a talk titled “<a href="https://www.mdaconference.org/abstract-library/ptp%cf%83-mediated-pi3p-regulation-as-a-therapeutic-strategy-for-c9orf72-als-ftd/">PTP [sigma]-Mediated PI3P Regulation as a Therapeutic Strategy for 9ORF72-ALS/FTD</a>” at the Muscular Dystrophy Association (MDA) 2024 Clinical and Scientific Conference, held last week in Florida and virtually.
[recommended-reading id=86923]
<h3>Seeking treatment strategies for genetic ALS due to C9ORF72 mutations</h3>
Though the <a href="https://alsnewstoday.com/causes-of-als/">causes of ALS</a> are not fully understood, genetic mutations are responsible for some cases of the disease. Mutations in the gene C9ORF72 are the most common genetic cause of ALS.
Disease-causing mutations in C9ORF72 lead to the production of small proteins called dipeptide repeats, or DPRs. These small proteins can cause <a href="https://alsnewstoday.com/news/molecular-traps-may-thwart-als-nerve-damage-from-gene-mutations/">toxic effects in cells</a>, and it’s thought that the toxic impacts of DPRs in nerve cells are the main reason that C9ORF72 mutations cause disease. One of the most toxic C9ORF72-derived DPRs is called poly-GR (poly-glycine-arginine).
With an eye toward identifying potential treatment strategies, Zhang and colleagues set out to find other genes that could modulate the toxic effects of poly-GR. The team conducted a screen in which the scientists basically inactivated random genes in nerve cells, then expressed poly-GR.
The toxic protein killed most, but not all, of the cells, and the researchers looked to see which genes had been inactivated in cells that survived.
&#8220;When you knock down these genes, it can significantly improve [poly]-GR-expressing neuron survival,&#8221; Zhang said.
One of the genes identified by this screen was PTP sigma, which provides instructions for making a protein with the same name. This protein is known to be involved in regulating the development and activity of nerve cells and also activates in a cellular recycling process called autophagy, helping it catch the researchers&#8217; attention.
In further experiments, the team confirmed that reducing PTP sigma protein levels led to better survival in nerve cells expressing toxic poly-GR. Then they set out to identify exactly why this was happening.
The team showed that altering PTP sigma didn&#8217;t affect levels of the toxic poly-GR itself, which Zhang said suggests that &#8220;this rescue effect is not coming from lowering [levels of poly]-GR.&#8221; Instead, the beneficial effect of reducing PTP sigma &#8220;has to be associated with other functions related to PTP sigma,&#8221; Zhang said.
The PTP sigma protein is known to be important for regulating the activity of another protein called PI3P, which is important for coordinating shipments of molecular cargo between different parts of nerve cells. This includes the movement of unwanted or faulty proteins or cellular components into lysosomes, the cell&#8217;s recycling centers — needed to eliminate the toxic protein clumps that build up in ALS.
The scientists found that expressing poly-GR in nerve cells reduced levels of PI3P — but reducing PTP sigma reversed this effect. This suggests that &#8220;maybe PI3P level is important for neuron survival,&#8221; Zhang said.
[recommended-reading id=83790]
<h3>Tests in cell models showed nerve-protecting effects</h3>
Further supporting this idea, the researchers showed that reducing PTP sigma was no longer protective when cells were treated with a PI3P-blocking drug. And conversely, treating cells with a compound that activates PI3P boosted survival in the face of toxic poly-GR.
&#8220;This is showing that the PI3P levels is critical for neuron survival with the presence of [poly]-GR,&#8221; Zhang said.
Additional tests in cell models showed that boosting the early endosomal pathway, which is one of the major molecular pathways that PI3P participates in to help move molecular cargo, had similar nerve-protecting effects to reducing PTP sigma or increasing PI3P.
These findings suggest that it&#8217;s this particular pathway that&#8217;s helping protect cells against poly-GR in these models — pointing to this pathway as a potential treatment target for C9ORF72-related ALS.
The researchers then conducted experiments in mice to see if a drug that blocks PTP sigma could reduce disease activity in animals expressing toxic poly-GR. The results showed that reducing PTP sigma led to less nerve death and less neuroinflammation, as well as better scores on tests of motor function.
Altogether, the scientists concluded, the results suggest a new biological strategy for treating this genetic form of ALS that warrants further study.

MDA 2024: Blocking protein shows promise for genetic form of ALS

The recent conditional approval of <a href="https://alsnewstoday.com/ionis-sod1-rx-biib067/">Qalsody</a> (tofersen) for adults with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) who carry mutations in the SOD1 gene is a major cause for celebration, according to the <a href="https://www.mda.org/">Muscular Dystrophy Association</a> (MDA).
The therapy <a href="https://alsnewstoday.com/news/fda-approves-tofersen-now-qalsody-treatment-adults-sod1-als/">earned accelerated approval</a> from the U.S. Food and Drug Administration (FDA) last week, making it the first to target a genetic cause of the disease to be approved.
The organization funded early research toward developing Qalsody for SOD1-associated ALS, which is estimated to affect about 330 people in the U.S. Its approval gives people with this rare form of the disease a new &#8220;treatment option,&#8221; according to the MDA.
“The approval of Qalsody is a turning point in therapy development for ALS as it represents the first therapy to target a genetic cause of the disease,” Sharon Hesterlee, PhD, chief research officer at MDA, said in a <a href="https://www.globenewswire.com/news-release/2023/04/25/2654417/0/en/Muscular-Dystrophy-Association-Celebrates-FDA-Approval-of-Biogen-s-Qalsody-for-Treatment-of-SOD1-ALS.html">press release from the organization</a>. &#8220;It’s gratifying to see a strategy that we and other organizations funded substantially in earlier stages maturing into a real solution for people living with this genetic form of ALS. It represents the fulfillment of the promise of effective genetic medicines for ALS patients and their families.&#8221;
Qalsody is expected to  be available to healthcare providers in the U.S. in the coming days, although its availability may vary as providers learn about it and adopt its use in their individual clinics, Biogen, the therapy&#8217;s developer, said in a <a href="https://investors.biogen.com/news-releases/news-release-details/fda-grants-accelerated-approval-qalsodytm-tofersen-sod1-als">press release announcing</a> the approval.
The company has launched a patient support services program, which can be accessed on the <a href="https://www.qalsody.com/">therapy&#8217;s website</a>. The program supports patients as part of their treatment, providing financial and insurance assistance, as well as education about the therapy.
“Since SOD1 mutations were first identified as a cause of ALS 30 years ago, the familial ALS community has been searching for genetically targeted treatments. Qalsody offers families who have lost generation after generation in the prime of their life to this devastating disease a therapy targeting the underlying cause of SOD1-ALS,&#8221; said Jean Swidler, chair of Genetic ALS &amp; FTD: End the Legacy.
Mutations in the SOD1 gene lead to the production of a toxic form of the SOD1 protein that forms clumps and causes nerve cell damage.
Qalsody is designed to lower SOD1 levels by targeting SOD1&#8216;s messenger RNA (mRNA) — an intermediate molecule needed for protein production — and marking it for degradation. Reducing the protein&#8217;s production should slow disease progression.
The therapy is approved at a dose of 100 mg via intrathecal injection — into the spinal canal — once a month following two initial loading doses.
[recommended-reading id=73945]
<h3>What led to Qalsody&#8217;s approval?</h3>
About eight months ago, the FDA <a href="https://alsnewstoday.com/news/fda-expected-decide-tofersen-approval-sod1-als-january/">agreed to review</a> Qalsody under its accelerated approval pathway, which lets it give conditional approval to a treatment based on early clinical trial data that indicates it&#8217;s safe and likely efficacious.
The FDA&#8217;s decision was based largely on biomarker data from the <a href="https://clinicaltrials.gov/ct2/show/NCT02623699">Phase 1/2/3 VALOR clinical trial (NCT02623699)</a> and its ongoing <a href="https://clinicaltrials.gov/ct2/show/NCT03070119">open-label extension study (NCT03070119)</a> that showed significant <a href="https://alsnewstoday.com/news/early-tofersen-treatment-may-slow-sod1-progression-valor-study/">reductions in blood levels of neurofilament light chain</a> (NfL), a biomarker of nerve cell damage.
The Phase 3 data indicated Qalsody <a href="https://alsnewstoday.com/news/phase-3-tofersen-trial-fails-slow-sod1-als-trends-hopeful-valor-trial/">failed to slow functional declines</a> for patients, however, but additional data spanning the trial and the extension phase showed <a href="https://alsnewstoday.com/news/early-tofersen-treatment-may-slow-sod1-progression-valor-study/">slower disease progression</a> for those who&#8217;d been using it longer. Moreover, early reductions in blood NfL levels were predictive of <a href="https://alsnewstoday.com/news/fda-approves-tofersen-now-qalsody-treatment-adults-sod1-als/#:~:text=predicted%20slower%20reductions%20in%20ALSFRS%2DR%20scores">slower functional declines</a>.
An FDA advisory committee last month <a href="https://alsnewstoday.com/news/panel-favors-tofersen-biomarker-data-mixed-on-efficacy-sod1-als/">unanimously agreed</a> these NfL level reductions were likely able to predict the treatment&#8217;s clinical efficacy, which may have supported the FDA&#8217;s ultimate approval.
Qalsody is now the first ALS therapy to be approved based on biomarker data.
“We’re excited to celebrate this milestone which brings the very first targeted treatment option to the SOD1-ALS community. This approval shows the FDA acting flexibly and progressively by using the accelerated approval pathway, innovative trial designs, and listening to the patient community to determine this treatment is safe and effective,&#8221; said Paul Melmeyer, vice president of public policy and advocacy at the MDA.
<h3>Continued Qalsody approval hinges on additional data</h3>
Qalsody&#8217;s continued approval may be contingent on additional data that supports its efficacy. Data from the ongoing <a href="https://clinicaltrials.gov/ct2/show/NCT04856982">Phase 3 ATLAS (NCT04856982)</a> trial are expected to fulfill that requirement.
ATLAS is <a href="https://clinicaltrials.gov/ct2/show/NCT04856982#contacts">recruiting</a> about 150 adults with SOD1 mutations associated with rapidly progressing ALS. Eligible participants will not yet have symptoms, but will show signs of nerve cell damage, reflected by high NfL levels.
Participants will be randomly assigned to receive either Qalsody (100 mg) or a placebo at the approved dosing schedule for up to two years, with the main goal being to determine whether the treatment can prevent symptoms from emerging.
Top-line data are expected in 2026. More confirmatory trials may be needed if the findings aren&#8217;t positive.
While Qalsody&#8217;s approval covers adults with SOD1-ALS, Sunny Brous, founder of SunnyStrong and an ALS patient, said the approval benefits all ALS patients.
“Any win for a subgroup of ALS is a win for the entire community,&#8221; Brous said. &#8220;We are all thankful for steps towards a cure.”

Tag: Genetic ALS

MDA 2024: Blocking protein shows promise for genetic form of ALS

Qalsody’s conditional OK for genetic cause of ALS hailed as new ‘option’