The Royal Music & Ar Group

Breaking Ground: New Treatments for Ultra-Rare Neurodegenerative Diseases

The landscape of rare neurodegenerative diseases—conditions like ALSP, Niemann-Pick C, X-ALD, CHAPLE, and ultra-rare genetic forms of ALS—is transforming rapidly thanks to advances in gene silencing, cell replacement, and drug repurposing.

1. Microglial Replacement Reverses ALSP Progression

A study published in July 2025 reported remarkable results using traditional bone marrow transplantation (BMT) to replace mutated microglia in patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). In eight treated patients, disease progression halted—and some saw stabilization or improvements in motor and cognitive function—for up to two years post-transplant.

The approach exploits the patients’ inherent CSF1R mutation, which suppresses their own microglia’s competitiveness, allowing donor-derived microglia to engraft efficiently and outcompete dysfunctional cells. A larger clinical trial is underway, and researchers believe this paves the way for microglial cell replacement therapies in other microglia-associated diseases like Alzheimer’s and Krabbe disease.

2. Levacetylleucine Gains FDA Approval for Niemann-Pick C

In September 2024, the FDA approved levacetylleucine (trade name Aqneursa), the first oral therapy approved for Niemann-Pick disease type C, a rare genetic neurodegenerative disorder in children. The L-form of acetylleucine showed measurable improvements in neurological symptoms and quality of life in clinical studies, with manageable side effects. This marks a significant milestone for treating phenotypes of lysosomal storage disorders.

3. Precision ASOs and Gene Therapies Advance in ALS and Huntington's

Tofersen (Qalsody), an antisense oligonucleotide targeting SOD1 mutations in ALS, received FDA approval in April 2023 (and EU approval in May 2024). It remains the first-in-class therapy for SOD1-ALS, demonstrating modest slowing of disease progression.

A recent case series featured antisense therapy against FUS mutations in rare ALS. Two patients saw unexpected recovery, including restored mobility and breathing independence, along with an 83% decrease in neurofilament light chain—an indicator of nerve damage.

For Huntington’s disease, allele-selective ASOs such as WVE-003 have shown efficacy in lowering mutant huntingtin protein while preserving the normal allele. Wave Life Sciences’ SELECT-HD trial revealed strong biomarker changes and good tolerability as of mid-2024.

Additionally, uniQure’s AMT-130 (an AAV5-delivered microRNA therapy) received FDA Breakthrough Therapy designation after demonstrating up to 80% progression slowing in early trials.

When combined with CRISPR-based approaches being developed in academic labs to target HTT mutation directly, the future for HD gene therapies looks increasingly promising.

4. Novel Biotech Platforms and Antisense Drugs Reach Into Rare Diseases

PrimeC, from NeuroSense, showed a 32.8% slowing of ALS progression and a survival benefit trend of 58% in a Phase IIb trial, leveraging modulation of miRNA expression and iron metabolism. Phase III is projected to begin mid-2025.

Biotech company Celosia Therapeutics, affiliated with Macquarie University, secured $16.8M to advance CTX-1000, a therapy targeting toxic TDP-43 protein in ALS, into human trials (late 2025 launch).

At the NIH BRAIN initiative, research has developed gene-delivery “trucks” (AAV-based vectors) capable of precise cell-type targeting in the brain and spinal cord, allowing safer and more effective gene activation. These tools are being made broadly available for rare neurodegenerative therapeutic research.

5. Drug Repurposing and Biomarker Advances

UCSF-led research screened 1,300 FDA-approved drugs using AI and computational modeling to find letrozole and irinotecan, two cancer drugs, which reversed neurodegeneration and restored memory in Alzheimer’s mouse models. Real-world medical record analysis also indicated reduced Alzheimer’s risk among users. Researchers think these findings accelerate clinical trial timelines for human studies.

Long-term use of HIV-related NRTIs correlated with a 6–13% annual reduction in Alzheimer’s risk in a cohort of over 270,000 adults. Researchers are advancing K9, a next-generation inflammasome inhibitor, into trials to prevent Alzheimer’s onset.

The Global Neurodegeneration Proteomics Consortium (GNPC) has built a dataset of 250 million protein measurements across thousands of samples, identifying novel biomarkers for Alzheimer’s and Parkinson’s. This open data resource accelerates new therapeutic target discovery and early diagnostics.

6. Success Stories from India: CHAPLE and X-ALD Treatments

In India, pozelimab, a monoclonal antibody, is being used under expert guidance to treat a child with CHAPLE disease (CD55 deficiency). Fewer than 100 cases globally exist, and the treatment combines expertise from global registries to bring hope to a formerly untreatable condition.

Meanwhile in New Delhi, a critically ill 7-year-old with X-ALD received a half-HLA matched stem cell transplant from his father. Despite severe complications—including graft-versus-host disease—the procedure led to full donor cell engraftment and early neurological recovery after 200 days, underscoring the power of early diagnosis and advanced care.