Innovative Clinical Trials Are Enhancing Patient Outcomes in Neurodegenerative Diseases

By Abanti Chattopadhyay, PhD

Functional neurosurgery is a specialized and rapidly growing field that aims to restore neurological function in various neurological and psychiatric disorders. It uses surgical ablation, resection or neuromodulation to alter brain, spinal cord, and nerve activity. Disorders include movement disorders, Parkinson’s disease (PD), essential tremor, dystonia, chronic pain, and epilepsy, among others.

Dr. Amir H. Faraji, Assistant Professor of Neurosurgery and Program Director of the Stereotactic and Functional Neurosurgery Fellowship at Houston Methodist, is a neurosurgeon focused on deep brain stimulation (DBS), neuromodulation, spinal cord stimulation, epilepsy surgery, peripheral nerve decompressions, nerve transfers, brain-computer interfaces and extended-reality implementations. He is developing new techniques and methodologies to improve patient outcomes for neurodegenerative diseases.

One of the methodologies Dr. Faraji uses to treat neurological disorders is the adeno-associated virus (AAV) gene therapy. AAVs are small viruses used for in vivo gene transfer; they are not known to cause any diseases in humans. This makes them an ideal vector for gene therapy.

AAV vectors are being studied for their potential in treating various diseases, including PD, epilepsy, Alzheimer’s disease, spinal muscular atrophy and even some cancers.

One of the genes used in AAV gene therapy is the glial cell line-derived neurotrophic factor (GDNF). GDNF is crucial for the survival, maintenance and regeneration of specific neuronal populations in the adult brain. GDNF has garnered considerable attention as a potential therapeutic molecule for the treatment of PD due to its ability to promote the survival of various neuron types.

PD is one of the most common neurodegenerative ailments with complex pathologies and mortality that has been increasing over time.

The AAV gene therapy with GDNF involves delivering a naked AAV capsule that carries GDNF instead of any active virus proteins into the human brain. The virus capsule is taken up by the cells, and the GDNF DNA gets incorporated into the human host DNA, leading to GDNF protein expression.

The blood-brain barrier precludes delivery of the AAV to the brain via intravenous administration. Hence, AAV gene therapy for neurologic ailments relies on magnetic resonance imaging (MRI)-guided precise delivery to the brain.

“The patient lies face down in the MRI scanner, and we pass a thin catheter into the brain that is the diameter of a strand of spaghetti using a few targeted points in the back of the head. The gene therapy agent is then injected into the brain through these catheters in the relevant target area," explains Dr. Faraji. "The procedure takes several hours, and we visualize the MRI infusions in real time, which allows us to guide the catheters and monitor the infusion process precisely. This is done for gene therapy as well as for cell therapy. In the latter case, instead of delivering or injecting DNA, we can inject stem cells into the brain in the same areas."

“Having the unique ability to do MRI-guided surgery means that we have access to these new avenues of patient care,” adds Dr. Faraji.

This promising methodology is often referred to as convection-enhanced delivery. It offers targeted and homogenous delivery of the genetic material, diminishes systemic toxicity, and bypasses the blood-brain barrier. However, this procedure is invasive, and the delivery volume is limited.

Houston Methodist is one of a handful of surgical sites as part of a multicenter clinical trial from AskBio — a leading, clinical-stage gene therapy company dedicated to developing AAV gene therapies for genetic and complex disorders. Faraji has successfully collaborated with AskBio’s gene therapy trials for PD.

AskBio is currently recruiting for an ongoing phase II, randomized, double-blind, surgery controlled study of the efficacy and safety of intraputaminal AAV2-GDNF in the treatment of adults with moderate stage PD.

Dr. Faraji is actively engaged in performing deep brain stimulation (DBS) as well for the treatment of various disorders, including PD. DBS is a surgical procedure that involves implanting electrodes into specific areas of the brain to deliver electrical impulses, which help regulate abnormal brain activity associated with dystonia, PD, other movement disorders, and neuropsychiatric disorders.

“This is really exciting. As you can imagine, there are so many Parkinson’s disease patients who don't necessarily want a brain simulator or device implanted in their bodies. We have amazing deep brain stimulation devices and safe procedures, but it's a different approach from gene therapy. What’s great about the gene therapy approach is that you can help the body heal itself,” Dr. Faraji comments.

Here are additional areas of research focus:

• Dr. Faraji and the neurosurgery team use Gamma Knife surgery — a type of non-invasive stereotactic radiosurgery to manage brain tumors and metastases, arteriovenous malformations, and pain or movement disorders. This method uses focused beams of radiation to precisely target the affected area while minimizing damage to the surrounding healthy tissue.
• Dr. Faraji and his team investigate key biophysical properties of molecular transport in the extracellular space of the brain that may impact the efficacy and control of drug delivery using stereotactic methods.
  
  

In his Clinical Innovations Laboratory, which is part of the Center for Neural Systems Restoration in the Department of Neurosurgery, Dr. Faraji and his team are building integrative neural interventions that improve human-centered outcomes. The team leverages translational innovations in electrokinesis, neural interfaces, precision robotics, and medical extended reality applications.

Furthermore, Dr. Faraji is investigating epilepsy outcomes from large data sets. Dr. Faraji and his team also stimulate and record from the brain during diagnostic brain mapping, epilepsy surgeries, and epilepsy monitoring. Efforts are aimed at understanding how epilepsy propagates in the brain networks, and also how the brain stimulation at one site can impact other sites of the brain.

“Houston Methodist is the center of excellence for drug delivery and cell therapy, and we have all the available infrastructure and expertise to do this accurately and safely in patients with a wide range of neurodegenerative disorders," comments Dr. Faraji. "We are involved in high-level clinical trials and standard-of-care procedures to try to improve the quality of life in patients with these neurological conditions. That's the goal of my practice and program, whether it's stroke, spinal cord injury, tremor, Parkinson's disease, epilepsy or nerve issues. To develop the breadth in the gamut of these neurological diseases requires specialized practice and the kind of infrastructure that I think only exists in places like Houston Methodist."

For further information on Dr. Faraji’s research, please see the following:

Rajendran, S., Bhenderu, L. S., Cruz-Garza, J. G., Patterson, J. D., Kumar, S., Gupta, P., Hassan, T., Taghlabi, K. M. & Faraji, A. H. Lead-Shift Error and Pneumocephalus in Awake, Robotic Deep Brain Stimulation Patients. Operative Neurosurgery. 2025, (Accepted/In press) 10.1227/ons.0000000000001642.

Mortezaei, A., Taghlabi, K. M., Al-Saidi, N., Amasa, S., Whitehead, R. E., Hoang, A., Yaeger, K., Faraji, A. H., Kadirvel, R. & Ghozy, S. Advanced targeted microsphere embolization for arteriovenous malformations: state-of-the-art and future directions. Neuroradiology. Apr 2025:  67, 4, p. 1009-1022 14 p., 821043.

Austerman, Ryan, and Amir Faraji. ID: 16322 Predictors of Favorable Discharge Disposition After Deep Brain Stimulation From a Large National Database. Neuromodulation 25, no. 5 (2022): S69-S70. https://doi.org/10.1016/j.neurom.2022.02.091

Taccola, G., Steele, A. G., Apicella, R., Oh, J., Dietz, V., Rajendran, S., Barber, S. M., Faraji, A. H., Horner, P. J. & Sayenko, D. G. Interactions between descending and spinal circuits on motor output.

Experimental Neurology. Oct 2025 : 392, p. 115347 115347.

Comparative analysis of Onyx, squid, and n-BCA in middle meningeal artery embolization for chronic subdural hematoma: a meta-analysis of randomized controlled trials. Mortezaei, A., Al-Saidi, N., Ghorbi, L., Taghlabi, K. M., Hajikarimloo, B., Habibi, M. A., Mohammadzadeh, I., Rahmani, R., Srinivasan, V. M., Burkhardt, J. K. & Faraji, A. H., 2025, (Accepted/In press) In: Neuroradiology.

Mortezaei, A., Hajikarimloo, B., Taghlabi, K. M., Yazdanian, F., Sameer, O., Rahmani, R., Faraji, A. H. & Elbabaa, S. K. Pediatric Head Gunshot Wounds, Clinical, Radiological, and Laboratory Findings: A Comprehensive Systematic Review and Meta-Analysis of 4012 Patients. 2025, (Accepted/In press) In: Neurocritical Care. n71.

Talukder, R., Taghlabi, K. M., Khan, R., Melhem, M., McManus, R., Hassan, T., Sankarappan, K., Patterson, J. D., Rajendran, S., Alsalek, S., Buccilli, B., Whitehead, R., Mortezaei, A. & Faraji, A. H. Predictive factors for postoperative complications in nerve grafting neurorrhaphies: A multispecialty analysis using NSQIP data. Clinical Neurology and Neurosurgery. Jul 2025:  254, 108918.