I am flying back from the EHDN meeting which is taking place in Stockholm, Sweden. As usual, I met with many colleagues, caregivers and relatives of patients. For a more in depth update on the meeting, please see HDBuzz (see link on the right). Today I wanted to update you on some new findings and about new timelines for clinical studies involving molecular therapies. The field of molecular therapies is perhaps, in an idealized sense, the most critical in terms of preventing disease onset or significantly altering disease course. It is, however, the most risky and indeed the road less traveled. Only in a few other indications have scientists and clinicians attempted to treat the diseases through molecular means (molecular here means using DNA or RNA as the therapeutic agents, rather than chemicals). In Parkinson’s disease, there have been some trials to deliver growth factors via viral delivery into the affected regions of the brain, and in ALS and SMA (spinal muscular atrophy), RNA-based therapeutics are being tested clinically through delivery into the intrathecal space (the fluid-filled space inside your spinal cord). HD is therefore probably at the forefront of these approaches, both in terms of the stage of the therapeutics as well as the breadth of approached being considered. Three major programs are close to entering clinical trials, and probably in this order based on expected IND filings (aside from unwanted, unexpected findings which might delay or prevent these trials): Medtronic will be taking an siRNA targeting both alleles of Huntingtin (HTT) into the clinic through direct delivery (via a catheter and a pump) into the putamen (a critical area of the brain which degenerates in HD and which is largely involved in motor control); ISIS Pharmaceuticals will deliver an antisense oligonucleotide targeting both alleles of HTT, to be delivered in the intrathecal space, which they expect will lower HTT expression broadly in the cortex; and finally, Sangamo Biosciences, who recently entered into a collaboration with Shire Pharmaceuticals to develop an allele-selective DNA-targeting zinc finger protein repressor, which would be administered via viral delivery. I am expecting these therapies to begin trials in the period of 2013-2015. These are exciting times in neuroscience and for HD.
These are 3 companies using 3 different technologies, and with different visions for how to deliver and treat HD; all innovative, all potentially impactful, and all risky.
We are indeed treading new frontiers in medicine.
There are several important questions that remain to be answered (and which will be a main focus of my research and that of my colleagues over the next few years) about these approaches: is sustained lowering of both the mutant and the normal HTT protein levels detrimental due to the critical function of the normal HTT protein in the brain? If we manage to circumvent this potential issue, what region of the brain is most important in delaying symptom progression or in restoring function? (The cortex, the basal ganglia, or other brain regions?)
In terms of the first question, there is reason to be extremely optimistic. Recent work by Beverly Davidson (who presented her work at the EHDN meeting) has shown thta this approach is tolerated well in non human primates (rhesus monkeys) up to 6 months when both copies of Huntingtin are repressed in the striatum. In addition, all 3 companies above and their academic collaborations, have now developed ways to selectively modulate expression of the mutant allele, without affecting the normal allele significantly, at least in human cells. Whether these reagents will be optimized sufficiently and will retain their discriminatory ability in vivo in the human brain remains to be seen, but it is certainly cause for renewed enthusiasm. Recent work by David Corey’s group, at the University of Texas Southwestern Medical Center (in collaboration with ISIS and Alnylam), has demonstrated how new modifications in RNA therapeutics can achieve this selectivity against mutant vs. normal Huntingtin RNA.
In the CHDI/Sangamo collaboration, which I managed for over a year now, the lead program has delivered a therapeutic which lowers expression of HTT protein in patient-derived cells (in the low 40s repeat range) without modulating expression of the normal protein. In my opinion, Sangamo’s allele selective approach will be the first in starting clinical trials based on the fast progression of this work, and the existing experience in the PD field with using viral delivery in the clinic. This approach has shown that a type of virus (AAV1/2) is well tolerated up to 2 years in humans, and 10 years in primates.
A fundamental difference in the approach of these 3 companies is the ‘target’ – Sangamo’s technology modulates expression through direct binding of their agent (a ‘ZFP’) to the Huntingtin regulatory domains in the genomic DNA, and stops the production of both the Huntingtin RNA and protein. The other 2 technologies target the Huntinting RNA for degradation, but it is made. There is some reason for concern in the latter approaches, as presented during the EHDN meeting in Stockholm. There is evidence that some toxicity in the polyglutamine disorders (and HD) might arise from the Huntingtin RNA itself (versus the HTT protein). Therefore, targeting the DNA rather than the RNA might be more effective, all else being equal.
Another reason for concern is the recent finding by Gill Bates, one of CHDI’s premier collaborators, of the misplicing of the huntingtin RNA. Splicing is a molecular process by which longer RNA molecules encoded by a given gene are processed to encode the final elements which will produce a protein. Huntingtin is an extremely large gene, with many splicing sites. What Gill just reported at the meeting was that a truncated, shorter version of the RNA can be produced through splicing. This shorter version of the RNA (which importantly is NOT targeted by the existing RNA directed therapeutics) generates a very toxic, exon 1 fragment of HTT protein. If this is indeed a phenomenon of relevance to the disease in humans, then the existing RNA based therapies might be less efficacious than desired. This is a set of findings of critical importance to me, and one that deserves independent verification from others, and in-depth evaluation in human patients.
Finally, the second question deserves some attention: for the most part, I have had little input into the decision of where to lower HTT expression. It is only recently that I have had access to the ‘tools’ necessary to answer this question, at least in rodent models of HD. The basal ganglia is a region that degenerates rapidly in HD, and is a critical area of the brain involved in information processing and action selection. HD is clearly a basal ganglia disorder. It makes sense, therefore, to attempt to lower HTT levels there. However, some questions remain: is this area too affected in Stage 1 or 2 patients, where the first clinical trials will be conducted? Also, the complexity of the three-dimensional geometry of the basal ganglia, might not allow clinicians to lower HTT in the entire circuitry affected. This might be important as this ‘geography’ is essential in determining the functional impact of these potential therapies. Another ‘concern’ (not substantiated yet by any means) is that in spite of lowering HTT levels in the basal ganglia, the damage caused by mutant HTT is too significant in other regions to be ‘rescued’ or ‘minimized’ by a focal approach. This is equivalent to trying to affect the European financial crisis by targeting the US market or the Chinese market – hopefully it will have an impact but we are not sure it will. This is the landscape we have to work in. Not an easy choice in light of scant data to support our ‘instinctual decisions’.
The ISIS approach targets the cortex, this broad, large landscape essential to human nature- there is evidence for targeting this area, recently being communicated to CHDI by William yang of UCLA. He has taken a genetic approach to understand what region of the brain is most responsible for the symptoms observed in a mouse model of HD (the BAC-HD mouse model). Without going into a lot of details, he has shown that in order to prevent all symptoms from developing, one needs to affect HTT levels in the basal ganglia and the forebrain (which includes the cortex). However, affecting only the cortex in his mouse model seems to have a more significant effect than lowering HTT in the striatum only. These data strengthen cortical targeting of HTT expression as an approach to ameliorate, or slow, symptom development in HD. I presume this work will be published shortly.
So, to summarize, the next 2-3 years will be critical to HD therapeutic development, as all these efforts lead to clinical trials. Even though the first trials will be essentially focused on safety, the development of new technologies, and our understanding of how to modify the disease course, will be fundamental to leading the field of molecular therapies for brain disorders. I remain very optimistic, even if cautiously so, about these approaches and about how much we will learn about the HD brain during this period of extreme excitement for those of us whose lives have been affected by HD.
Good day, and speak to you soon.